Treating lung inflammation with agonists of the adenosine A2A receptor: promises, problems and potential solutions.

Adenosine A(2A) receptor agonists may be important regulators of inflammation. Such conclusions have come from studies demonstrating that, (i) adenosine A(2A) agonists exhibit anti-inflammatory properties in vitro and in vivo, (ii) selective A(2A) antagonists enhance inflammation in vivo and, (iii) knock outs of this receptor aggravate inflammation in a wide variety of in vivo models. Inflammation is a hallmark of asthma and COPD and adenosine has long been suggested to be involved in disease pathology. Two recent publications, however, suggested that an inhaled adenosine A(2A) receptor agonist (GW328267X) did not affect either the early and late asthmatic response or symptoms associated with allergic rhinitis suggesting that the rationale for treating inflammation with an adenosine A(2A) receptor agonist may be incorrect. A barrier to fully investigating the role of adenosine A(2A) receptor agonists as anti-inflammatory agents in the lung is the side effect profile due to systemic exposure, even with inhalation. Unless strategies can be evolved to limit the systemic exposure of inhaled adenosine A(2A) receptor agonists, the promise of treating lung inflammation with such agents may never be fully explored. Using strategies similar to that devised to improve the therapeutic index of inhaled corticosteroids, UK371,104 was identified as a selective agonist of the adenosine A(2A) receptor that has a lung focus of pharmacological activity following delivery to the lung in a pre clinical in vivo model of lung function. Lung-focussed agents such as UK371,104 may be suitable for assessing the anti-inflammatory potential of inhaled adenosine A(2A) receptor agonists.

Correlation between baseline plasminogen activator inhibitor levels and clinical outcome during therapy with tissue plasminogen activator for acute myocardial infarction.

Baseline plasminogen activator inhibitor (PAI) levels were examined for their influence on the responses to thrombolysis with recombinant tissue plasminogen activator (rt-PA) administered for acute myocardial infarction during the Thrombolysis and Myocardial Infarction (TAMI)-I study. Baseline PAI activity was 19 +/- 21 IU/ml (normal less than 5 IU/ml) and baseline PAI-1 antigen 54 +/- 53 ng/ml (normal 27 +/- 16 ng/ml), confirming previous findings of elevated PAI levels during acute myocardial infarction. Among clinical outcomes, lower PAI-1 antigen levels correlated weakly with greater patency at the 90 min angiogram. Thus, high baseline plasma PAI-1 levels may be detrimental to reperfusion with t-PA. There was no correlation with other major in-hospital clinical outcomes including reocclusion at the 7-10 day angiogram, survival to discharge, or bleeding. During the follow up period of 2.0 +/- 0.4 years, no relationship between baseline PAI levels and post-discharge reinfarction was observed.