Effects of short-acting bronchodilators added to maintenance tiotropium therapy.

BACKGROUND: Combining bronchodilators has been shown to be beneficial in patients with COPD. The additive effects of short-acting bronchodilators added to maintenance tiotropium therapy, however, are unknown. METHODS: Following 3 weeks of tiotropium pretreatment, 60 patients with COPD (FEV1 40% of predicted) participated in a randomized, placebo-controlled study to assess add-on bronchodilator effects of ipratropium bromide (40 microg) or fenoterol (200 microg). Short-acting bronchodilators were added as a single dose 2 h and 8 h after tiotropium dosing. Serial lung function tests were performed over 9 h. RESULTS: The peak FEV1 add-on response within 6 h with fenoterol was significantly greater than with placebo (137 mL) or ipratropium (84 mL); the response with ipratropium was slightly but significantly larger than with placebo (52 mL). One hour after the second dose of the test drugs, a similar order of treatment responses was found. The peak FVC add-on response was significant for fenoterol (249 mL) but not for ipratropium (42 mL). CONCLUSIONS: In conclusion, both short-acting bronchodilator classes were effective when added to maintenance treatment with tiotropium. The addition of the beta2-adrenergic fenoterol provided greater additional bronchodilatation than the short-acting anticholinergic ipratropium. This is consistent with the expected effects of combining bronchodilators with different pharmacologic mechanisms. This randomized controlled trial was registered at www.clinicaltrials.gov (NCT00274066).

Preconditioning of rat hearts by adenosine A1 or A3 receptor activation.

Our study in rat hearts examined whether activation of adenosine A(1) or A(3) receptors improved functional recovery and reduced apoptosis resulting from low-flow ischemia. Prior to 30 min low-flow ischemia (0.6 ml/min; 6% of baseline flow), Langendorff rat hearts were preconditioned with two 5-min cycles of (a) ischemia (PC; n=7), (b) infusion of 250 nM adenosine A(1) receptor agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA; n=6), or (c) infusion of 50 nM adenosine A(3) receptor agonist N(6)-(3-iodobenzyl)-adenosine-5'-N-methyl-uronamide (IB-MECA; n=8). Recovery of function was improved in PC (71+/-3%), CCPA (68+/-6%) and IB-MECA (68+/-4%) groups compared to control hearts (46+/-5%; P<0.05). Cumulative release of total purines during ischemia-reperfusion was approx. 50% lower in PC, CCPA and IB-MECA groups compared to controls (P<0.05) and was significantly correlated to the percentage functional recovery (R(2)=0.55; P<0.05). The number of cytosolic histone-associated-DNA fragments, a hallmark of apoptosis and measured by Enzyme Linked ImmunoSorbent Assay (ELISA), was small and not different between groups after 30 min reperfusion. However, CCPA (0.6+/-0.1 absorbance units) and MECA (0.7+/-0.1 units; P<0.05 vs. PC) decreased apoptosis after 150 min reperfusion compared to PC (1.4+/-0.3 units) and control (1.2+/-0.1 units) hearts. This study shows that adenosine triggers protection of function in preconditioned rat hearts via both the adenosine A(1) and A(3) receptor. In clinical practice, pharmacological stimulation of adenosine A(3) receptors may be advantageous over adenosine A(1) receptor activation due to a lack of contractile side-effects. In contrast to ischemic preconditioning, pharmacological stimulation of adenosine A(1) or A(3) receptors reduced apoptosis. Furthermore, total purine release may serve as a marker of the degree of functional protection.