Thomas Aherne

The role of COX-2 inhibitors in lung cancer

BACKGROUND Human lung cancer is a major cause of death worldwide with few known effective therapeutic modalities. The isoenzyme cyclooxygenase 2 (COX-2) is an inducible inflammatory enzyme with increased activity evidenced in lung carcinoma. The objective was to determine the effect of a selective COX-2 inhibitor on proliferation and apoptosis rates in the Lewis lung (3LL) tumor cell line in vitro. METHODS First, 1 x 10(4) 3LL cells were plated in a 96-well plate. Cells were incubated for 24 hours with either a control or increasing doses of rofecoxib (0.1 mmol/L, 0.25 mmol/L, 0.5 mmol/L, 1.0 mmol/L, and 2.5 mmol/L) in complete Dulbeccos Modified Eagles Medium culture medium. Cell proliferation was measured using BrdU enzyme-linked immunosorbent assay. Next, 1 x 10(6) 3LL cells were similarly treated. Cells were permeabilized, immunostained with propidium iodide and apoptotic rates were measured using flow cytometry. Then, 5 x 10(4) cells were plated on a 24-well plate. Cells were incubated for 24 hours with either control or increasing doses of rofecoxib (0.1 mmol/L, 0.25 mmol/L, 0.5 mmol/L, 1.0 mmol/L, and 2.5 mmol/L) in complete culture medium. Supernatant was collected and lactate dehydrogenase was measured for cell necrosis using a cytotoxicity detection kit. RESULTS The selective COX-2 inhibitor rofecoxib resulted in a dose-dependent increase in apoptosis and dose and time-dependent growth inhibition in cell proliferation. However, rofecoxib did not cause cell necrosis. CONCLUSIONS There was a significant decrease in proliferation and increase in apoptosis of 3LL tumor cells when treated with the highly selective COX-2 inhibitor rofecoxib. COX-2 inhibitors may have a potential role to play in the treatment of lung carcinoma.

Impact of pacing modality and biventricular pacing on cardiac output and coronary conduit flow in the post-cardiotomy patient.

We have previously demonstrated the role of univentricular pacing modalities in influencing coronary conduit flow in the immediate post-operative period in the cardiac surgery patient. We wanted to determine the mechanism of this improved coronary conduit and, in addition, to explore the possible benefits with biventricular pacing. Sixteen patients undergoing first time elective coronary artery bypass grafting who required pacing following surgery were recruited. Comparison of cardiac output and coronary conduit flow was performed between VVI and DDD pacing with a single right ventricular lead and biventricular pacing lead placement. Cardiac output was measured using arterial pulse waveform analysis while conduit flow was measured using ultrasonic transit time methodology. Cardiac output was greatest with DDD pacing using right ventricular lead placement only [DDD-univentricular 5.42 l (0.7), DDD-biventricular 5.33 l (0.8), VVI-univentricular 4.71 l (0.8), VVI-biventricular 4.68 l (0.6)]. DDD-univentricular pacing was significantly better than VVI-univentricular (P=0.023) and VVI-biventricular pacing (P=0.001) but there was no significant advantage to DDD-biventricular pacing (P=0.45). In relation to coronary conduit flow, DDD pacing again had the highest flow [DDD-univentricular 55 ml/min (24), DDD-biventricular 52 ml/min (25), VVI-univentricular 47 ml/min (23), VVI-biventricular 50 ml/min (26)]. DDD-univentricular pacing was significantly better than VVI-univentricular (P=0.006) pacing but not significantly different to VVI-biventricular pacing (P=0.109) or DDD-biventricular pacing (P=0.171). Pacing with a DDD modality offers the optimal coronary conduit flow by maximising cardiac output. Biventricular lead placement offered no significant benefit to coronary conduit flow or cardiac output.

Prostacyclin and thromboxane levels in pleural space fluid during cardiopulmonary bypass

Prostaglandins exhibit a variety of cardiovascular actions that may affect the hemodynamic recovery of the ischemic myocardium after cardiopulmonary bypass. We have observed a decrease in the mean arterial pressure on autotransfusion of the accumulated pleural cavity fluid during operation. One aim of this study was to determine the concentrations of prostacyclin and thromboxane A2 in the pleural cavity fluid by measuring their stable metabolites, 6-keto-PGF1 alpha and thromboxane B2, respectively, in 8 consecutive patients undergoing myocardial revascularization, and to compare them with the arterial levels. A second aim was to quantify the hemodynamic effect of the pleural cavity fluid during operation. The concentration of 6-keto-PGF1 alpha in the pleural cavity fluid was significantly higher than the arterial concentration (mean, 21.6 +/- 18.2 ng/mL; p < 0.01). The concentration of thromboxane B2 was also raised compared with the arterial concentration (mean, 3.62 +/- 5.96 ng/mL; p < 0.2). The percentage fall in the mean arterial pressure was 29.7% +/- 8.86% (p < 0.02), which was transient and lasted 1 to 3.5 minutes. The hemoglobin concentration, potassium level, and pH were also measured. This study shows that the pleural cavity fluid during cardiac operations contains significant amounts of endogenous prostacyclin. Considering the potential benefit of prostacyclin on the recovering myocardium, we believe that this fluid should be transfused as a volume replacement, keeping in mind the transient phase of hemodynamic instability.

Dopexamine increases internal mammary artery blood flow following coronary artery bypass grafting

OBJECTIVE Vasoactive agents and inotropes influence conduit-coronary blood flow following coronary artery bypass grafting (CABG). It was hypothesized that dopexamine hydrochloride, a dopamine A-1 (DA-1) and beta(2) agonist would increase conduit-coronary blood flow. A prospective randomized double blind clinical trial was carried out to test this hypothesis. DA-1 receptors have previously been localized to human left ventricle. METHODS Twenty-six American Society of Anaesthesiology class 2-3 elective coronary artery bypass graft patients who did not require inotropic support on separation from cardiopulmonary bypass (CPB) were studied. According to a randomized allocation patients received either dopexamine (1 microg/kg per min) or placebo (saline) by intravenous infusion for 15 min. Immediately prior to and at 5,10 and 15 min of infusion, blood flow through the internal mammary and vein grafts (Transit time flow probes, Transonic Ltd.), heart rate, cardiac index, mean arterial pressure and pulmonary haemodynamics were noted. The data were analysed using multivariate analysis of variance. RESULTS Low-dose dopexamine (1 microg/kg per min) caused a significant increase in mammary graft blood flow compared to placebo at 15 min of infusion (P=0.028, dopexamine group left internal mammary artery (LIMA) flow of 43.3+/-14.2 ml/min, placebo group LIMA flow at 26.1+/-16.3 ml/min). Dopexamine recipients demonstrated a non-significant trend to increased saphenous vein graft flow (P=0.059). Increased heart rate was the only haemodynamic change induced by dopexamine (P=0.004, dopexamine group at 85.2+/-9.6 beats/min and placebo group at 71.1+/-7.6 beats/min after 15 min of infusion). CONCLUSION This study demonstrates that administration of dopexamine (1 microg/kg per min) was associated with a significant increase in internal mammary artery graft blood flow with mild increase in heart rate being the only haemodynamic change. Low-dose dopexamine may improve graft flow in the early post CABG period with minimal haemodynamic changes.