Similar con clusions were reached in studies where NFB signaling was ablated by stem cell replacement or gene therapy.It is unclear why NBD did not provide this same benefit to GRMD dogs.One possibility,given http://www.selleckchem.com/products/Sunitinib-Malate-(Sutent).html the develop ment of IgG antibodies,is that NBD could have been neu tralized in the later portion of the study,masking a potential enhanced regenerative response.Alternatively,species differences could play a role.Mdx mice undergo continual muscle regeneration throughout their lifespan.In contrast,muscle regeneration in dystrophic dogs and DMD patients diminishes over the progression of the dis ease,potentially due to their shorter telomere length and lower telomerase activity.Thus,it is likely that mdx satellite cells are more easily stimulated to expand than canine or human cells.

Perhaps,as discussed above in the context of the reduced level of hypertrophy,the relative reduction of necrosis in NBD treated dogs also may have led to a less pronounced Inhibitors,Modulators,Libraries regenerative response.As with Inhibitors,Modulators,Libraries any pre clinical treatment trial in an animal model,we were particularly interested in the safety profile of our product.Notably,NBD treatment in the murine models of DMD and in numerous other mouse and rat models of disease associated with NFB signaling had not reported any side effects.In our current 4 month GRMD NBD trial,several dogs demonstrated infusion re actions characterized by features of vasodilation and hypotension that appeared after about a month of treat ment.Although the mechanisms of action for these responses Inhibitors,Modulators,Libraries are not clear,signs were indicative of hypersen sitivity reactions.

Some treated dogs also had IgE Inhibitors,Modulators,Libraries and IgG antibodies reactive to NBD,lending further cre dence to a hypersensitivity reaction.Dogs have been used to model hypersensitivity reactions in humans and there is considerable overlap in mast cell function between the two species.It is also possible that immunoglobu lins could have resulted from foreign sequences Inhibitors,Modulators,Libraries in NBD,as the human version used for these studies differs from that of dogs by two amino acids at the amino terminal end.Safety studies testing a dog version of NBD are cur rently underway.It is noteworthy that a distinct infusion reaction was recently described in dogs with lymphoma that received a single injection of NBD at 0.5 and 1 mg Kg.A selective number of dogs developed moderate hypertension soon after the administration of NBD that resolved without treatment.

Curiously,this reaction is op posite of the hypotension we observed in this study.Because NBD mediated responses seen in normal selleck compound and diseased dogs may be linked to an immune reaction,ef forts are underway to initiate formal pre clinical toxicol ogy studies in non human primates,whose immune system more closely resembles man compared to dogs.In a 28 day repeat dosing non GLP study in non human pri mates,systemic infusion responses reported here in dogs were not observed.