RASONs: a novel antisense oligonucleotide therapeutic approach for asthma.

Inhalation based approaches enable the local delivery of antisense oligonucleotides (ASONs) to the respiratory tract and thus facilitate the ability of ASONs to target and modulate the activity of discordantly expressed respiratory disease genes. Studies involving EPI-2010, a respirable antisense oligonucleotide (RASON), targeting the adenosine A(1) receptor, a G-protein-coupled-receptor (GPCR) that plays an important role in the aetiology of asthma, demonstrate that ASON therapeutics can be delivered directly to the lung as an aerosol. EPI-2010 has been shown to inhibit adenosine A(1) receptor expression and significantly improve allergen-induced airway obstruction and bronchial hyper-responsiveness in animal models of human asthma. Absorption, tissue distribution, metabolism and excretion (ADME) and safety studies of aerosolised EPI-2010 suggest that phosphorothioate RASONs can be delivered to target respiratory tissues in low, safe, efficacious and long-acting doses. This supports the concept that RASONs offer the potential to address a variety of respiratory targets including those for which approaches employing systemic distribution and systemic bioavailability of the therapeutic agent may be undesirable. In addition, our studies with EPI-2010 indicate that the RASON approach may represent a technology that is uniquely positioned to address the challenges of the post-genome era in respiratory drug discovery, since it enables simultaneous in vivo target validation and antisense therapeutic discovery in an accelerated timeframe.

Cephalosporin-aminoglycoside synergistic nephrotoxicity: fact or fiction?

A review of synergistic nephrotoxicity associated with the concomitant administration of aminoglycoside and cephalosporin antibiotics is presented. A combination of these antibiotics is frequently administered in clinical practice as initial therapy in the treatment of gram-negative bacillary infection. The nephrotoxicity associated with cephalosporin/aminoglycoside administration in humans has been characterized as an acute tubular necrosis. Attempts to investigate this type of toxicity in animals using the rat as the model have revealed that the rat kidney is not affected by the aminoglycoside/cephalosporin combination in the same manner as the human kidney. The results from studies using the rat were not predictive of the nephrotoxicity encountered in humans, and cephalosporins actually appear to protect the rat from aminoglycoside-induced renal damage. The mechanism of the protective effect in rats and the toxic effects in man remain unknown. A species differentiation clearly exists between man and rats with respect to the nephrotoxic effects of aminoglycoside/cephalosporin combinations. The weight of present evidence indicates that, in man, an aminoglycoside/cephalosporin combination is synergistically nephrotoxic.