Anti-endotoxin, interleukin-1 receptor antagonist and anti-tumor necrosis factor antibody with arginine-free formulations for the treatment of hypotension

摘要

Methods and compositions for treating and inhibiting hypotension related to both endotoxin and cytokine-induced shock are provided. A therapeutic regimen useful in the present invention includes an arginine- free parenteral formulation administered with or followed by the administration of an anti-endotoxin antibody, an interleukin-1 or interleukin-2 receptor antagonist, an anti-tumor necrosis factor antibody or a combination thereof. Most preferably, the administration of an arginine-free parenteral formulation augments the anti-hypotensive effect of the various antibodies and antagonist described so as to provide an effective treatment for various forms of hypotension. The therapeutic regimens of the invention are proposed to provide for a decrease in nitric oxide synthase, and thereby an increase in blood pressure in vivo, particularly in animals with cytokine- and/or endotoxin-induced hypotension. The parenteral formulation of the therapeutic regimen and methods of the invention are arginine-free and provide a decrease in plasma arginine levels. Reduced plasma, serum, or tissue levels of arginine in the animal function to augment the hypertensive action of the various antibodies and antagonist to be administered concurrently or subsequent to the administration of the parenteral formulation. Limiting and/or eliminating substrate arginine for nitric oxide synthesis, coupled with limiting and/or eliminating induction of nitric oxide synthase activity with the antibodies and antagonists of the present invention, provides a regimen for treating and/or inhibiting hypotension attendant a variety of conditions and treatments, including chemotherapeutic agent therapy (IFN, TNF, IL-1, IL-2), septic shock, trauma, exposure to endotoxins or cytokines, or other conditions in which hypotension is attendant.