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NPC 15669 reduces mortality associated with sepsis in rats
L Noronha-Blob1, V C Lowe, L Otterbein
1Scios Nova Inc., Baltimore, Maryland.
The Journal of Pharmacology and Experimental Therapeutics
|November 1, 1993
Summary
N-[9H-(2,7-dimethylfluoren-9-ylmethoxy)carbonyl]-L-leucine (NPC 15669) effectively cured sepsis in rats by inhibiting leukocyte recruitment. This compound shows promise for treating septic shock, outperforming other anti-inflammatory drugs.
Area of Science:
- Pharmacology
- Immunology
- Sepsis Research
Background:
- Sepsis, particularly from fecal peritonitis, is a life-threatening condition characterized by uncontrolled inflammation and immune cell dysfunction.
- Leukocyte recruitment is a critical but potentially damaging component of the inflammatory response in sepsis.
- Existing anti-inflammatory drugs like aspirin and dexamethasone have limited efficacy in severe sepsis models.
Purpose of the Study:
- To investigate the therapeutic potential of N-[9H-(2,7-dimethylfluoren-9-ylmethoxy)carbonyl]-L-leucine (NPC 15669), a leukocyte recruitment inhibitor, in a rat model of sepsis.
- To evaluate the efficacy of NPC 15669 in enhancing survival and reversing sepsis-induced pathologies.
- To compare the effects of NPC 15669 with other anti-inflammatory agents and a non-inhibitory analog.
Main Methods:
- Rats with induced fecal peritonitis were treated with varying doses and schedules of NPC 15669, gentamicin, aspirin, dexamethasone, or an inactive analog.
- Survival rates and time to survival were recorded.
- Leukopenia and neutrophil infiltration into the small intestine were assessed to evaluate the compound's mechanism of action.
Main Results:
- NPC 15669 at effective doses (3 mg kg-1 hr-1 i.v. or 10 mg/kg bolus) cured all septic rats, achieving > 2-week survival, unlike gentamicin alone or lower NPC 15669 doses.
- NPC 15669 reversed leukopenia and significantly inhibited neutrophil infiltration, correlating with its survival-enhancing effects.
- While ibuprofen improved survival time, only NPC 15669 demonstrated a curative effect, even when administered therapeutically up to 6 hours post-sepsis induction.
Conclusions:
- NPC 15669, a specific leukocyte recruitment inhibitor, is highly effective in treating sepsis induced by fecal peritonitis in a rat model.
- The therapeutic efficacy of NPC 15669 is linked to its ability to modulate neutrophil infiltration and correct sepsis-induced leukopenia.
- These findings suggest that NPC 15669 holds significant potential as a therapeutic agent for septic shock.
