RESUMEN
Hemorrhage secondary to rupture of a brain arteriovenous malformations (AVM) is one of the initial manifestations, and the main cause of, morbidity and mortality in patients with this condition. Current treatment strategies include endovascular embolization with the goal of AVM obliteration and neurological preservation. In the transvenous endovascular embolization procedure, adenosine is the preferred agent to induce temporary hypotension and allow adequate AVM embolization. We describe the intraoperative management of an adenosine-resistant 38 year-old male who underwent a successful intracranial AVM embolization after concomitant administration of gradually increasing doses of nitroglycerin. This report suggests that nitroglycerin infusion can be combined with adenosine boluses to create a pronounced and dose-dependent hypotension in patients partially unresponsive to adenosine alone.
RESUMEN
L-Asparaginase is an enzyme successfully being used in the treatment of acute lymphoblastic leukemia, acute myeloid leukemia, and non-Hodgkin's lymphoma. However, some disadvantages still limit its full application potential, e.g., allergic reactions, pancreatitis, and blood clotting impairment. Therefore, much effort has been directed at improving its performance. A popular strategy is to randomly conjugate L-asparaginase with mono-methoxy polyethylene glycol, which became a commercial FDA approved formulation widely used in recent years. To improve this formulation by PEGylation, herein we performed cysteine-directed conjugation of the L-asparaginase subunits to prevent dissociation-induced loss of activity. The recombinant cysteine conjugation sites were introduced by mutagenesis at surface-exposed positions on the protein to avoid affecting the catalytic activity. Three conjugates were obtained using different linear PEGs of 1000, 2000, and 5000 g/mol, with physical properties ranging from a semi-solid gel to a fully soluble state. The soluble-conjugate exhibited higher catalytic activity than the non-conjugated mutant, and the same activity than the native enzyme. The cysteine-directed crosslinking of the L-asparaginase subunits produced a higher molecular weight conjugate compared to the native tetrameric enzyme. This strategy might improve L-asparaginase efficiency for leukemia treatment by reducing glomerular filtration due to the increase in hydrodynamic size thus extending half-live, while at the same time retaining full catalytic activity.