NOS2-specific inhibitors

Some NOS inhibitors have been used in research in humans. The nonselective inhibitor NMMA has been used in normals and in trials for septic shock (Bakker et al. 2004) and for migraine headache (Tepper et al. 2001). A phase 11 randomized, double-blind trial of NMMA to treat patients with shock associated with acute myocardial infarction revealed no beneficial or possibly deleterious effects (Alexander et al. 2(X)7). In a different trial, a pro-drug for the NOS2-specific inhibitor L-NIL was administered orally to normal individuals and to those with asthma. The drug reduced exhaled NO and had no effects on blood pressure, pulse, and respiratory function (Hansel et al. 2003). There have been numerous preclinical studies in non-human animals of a variety of nonselective and selective inhibitors. Several NOS 1-specific inhibitors have been studied in animal models of amyotrophic lateral sclerosis, Parkinson s disease, Huntington s disease, Alzheimer s disease, depression, and anxiety (Chabrier et al. 1999). 

Non-specific NOS inhibitors and NOS2-specific inhibitors either did not induce CLL eell death or indueed CLL eell death with EC50 values over 2000 p-M. In contrast, NOSl-specific inhibitors induced CLL cell death at much lower concentrations. In general, the lower the for inhibiting recombinant purified human NOSl, the more hkely the compound was to kill CLL cells (Levesque et al. 2008). 

Blasko et al. 2002)] block NO formation by NOS. NOS2-specilic inhibitors have been targeted for use in a variety of conditions, most prominently septic and cardiac shock, and arthritis. NOS 1-specific inhibitors have been targeted for use in psychiatric diseases sueh as depression and anxiety and for neurodegenerative diseases such as Alzheimer s disease and amyotrophic sclerosis (Chabrier et al. 1999). 

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