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

DETAILED DESCRIPTION The inventors herein propose uses of anti-TNF antibodies, anti-endotoxin antibodies, and cytokine receptor antagonists (e.
g.
, IL-1 receptor antagonist) in combination with arginine-free formulations in conceptually distinct approaches for the treatment of septic and cytokine-induced shock.
The arginine-free formulations may be conveniently supplied as either a parenteral formulation (to be administered intravenously) or as an oral formulation (to be administered enterally).
The most preferred embodiment of the parenteral formulation comprises a parenteral formula.
Since antibodies and receptor antagonists intervene early in the pathological response to cytokines, their optimal use requires anticipation of shock.
While administration of these agents could affect important biological events after the initiation of the biological response to endotoxin or cytokines, these agents do not block NO synthesis once the enzyme is induced.
Because NO production, once induced in smooth muscle cells, appears to persist for more than 16 hours after transfer to cytokine-free medium, antibodies and receptor antagonists are less likely to be effective at blocking or slowing NO synthesis once it has begun.
The recently reported potential benefit of a human monoclonal antibody against endotoxin in patients with septic shock associated with gram-negative bacteremia (Ziegler et al.
(1991) New England Journal of Medicine, 324:429) is best attributed to the prevention of further induction of cytokine mediators rather than to direct improvement of the existing cardiovascular profile.
In contrast, the inventors own work has demonstrated that nitric oxide synthase inhibitors or treatments designed to act to limit nitric oxide synthase substrate availability, act within minutes, even in severe shock.
The rapidity of the response to nitric oxide synthase inhibitors and to treatments designed to limit nitric oxide synthase substrate availability, and the fact that their efficacy is independent of the precipitating factor (i