Hydrolysis and Oxidation of NXY-059

Measurement of the aldehyde hydrolysis product of NXY-059, which I assume AZ has, may not suffice to resolve the issue. As the '527 patent and the literature detail, this is a complicated matter, involving both hydrolysis of NXY-059 and oxidation or photolysis of NtBHA to other products such as MNP, as well as reduction of the latter back to NtBHA and/or release of nitric oxide (with all that implies).

For example, the differences could have crept in not only due to differences in (say) storage, but also earlier due to differences in the synthesis used. E.g., AstraZeneca's US patent 6,512,143 details methods for inhibiting the oxidation of NtBHA to MNP during synthesis of NXY-059. Considering the large amounts of NXY-059 infused, only a little such "contamination" in the earlier trial might explain things.

Similarly, according to the '527 patent data, fresh NXY-059 may contain about 1% or so of the hydrolysis products natively. So, alternately, perhaps the drug formulations in SAINT-2 were "cleaned-up" to remove hydrolysis products produced in manufacture and storage.

Hopefully, AstraZeneca will directly address the issue of whether the formulation used in SAINT-1 was differently stored, packaged, or administered from that in SAINT-2. E.g., perhaps someone recalls a decrease in the size of the bottle and/or an increase in the concentration of NXY-059 between trials. Perhaps instructions went out to protect parenteral solutions from light exposure or to only make them up shortly before infusion. Or, maybe there are subtile differences between the way US hospitals and European hospitals handle infusions and infusion solutions. Such minutiae sometimes fall in the cracks and would mainly be the provence of nursing staff, infusion technicians, or hospital pharmacists and not of the principal investigators.

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