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Protective effects of a platelet activating factor (PAF) antagonist and its combined treatment with prostaglandin
Z Terashita1, G L Stahl, A M Lefer
1Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Abstract:
We have investigated the role of platelet activating factor (PAF) in the pathogenesis of a murine model of traumatic shock using CV-6209, a specific antagonist of PAF. CV-6209, at a dose of 1 mg/kg (i.v.) given after trauma, significantly improved survival rate at 150 min and overall survival time. Furthermore, the plasma accumulation of the lysosomal hydrolase, cathepsin D, and a cardiotoxic peptide, myocardial depressant factor (MDF), were also attenuated by CV-6209 in traumatic shock. Combined treatment employing low doses of CV-6209 [0.2 mg/kg, i.v. and prostaglandin (PG) E1, 0.8 microgram/kg/min] in this shock model was also examined. CV-6209 (0.2 mg/kg) or PGE1 (0.8 microgram/kg/min) alone at these doses showed only minimal effects on survival, or plasma cathepsin D or MDF activities. However, combined treatment with CV-6209 (0.2 mg/kg, i.v.) and PGE1 (0.8 microgram/kg/min) significantly improved survival rate at 150 min, overall survival time, and decreased the accumulation of plasma MDF. These results suggest that PAF may play an important pathophysiologic role in traumatic shock in rats. Moreover, combination therapy using a PAF antagonist and PGE1 may be useful for the treatment of traumatic shock.
Insights
Platelet activating factor (PAF) plays a key role in traumatic shock. Blocking PAF with CV-6209 improved survival and reduced harmful substances. Combination therapy with prostaglandin E1 enhanced these protective effects.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Trauma Medicine
Background:
- Traumatic shock involves complex pathophysiological processes.
- Platelet activating factor (PAF) is implicated in shock-related inflammation and injury.
- Understanding PAF's role is crucial for developing effective shock treatments.
Purpose of the Study:
- To investigate the role of PAF in a murine model of traumatic shock.
- To evaluate the efficacy of a PAF antagonist (CV-6209) in improving outcomes.
- To explore the potential of combination therapy with CV-6209 and prostaglandin E1 (PGE1).
Main Methods:
- Utilized a murine model of traumatic shock.
- Administered CV-6209, a specific PAF antagonist, at varying doses.
- Assessed survival rates, survival time, and plasma levels of cathepsin D and myocardial depressant factor (MDF).
- Investigated combined treatment with low-dose CV-6209 and PGE1.
Main Results:
- CV-6209 (1 mg/kg) significantly improved survival and survival time post-trauma.
- CV-6209 treatment attenuated plasma accumulation of cathepsin D and MDF.
- Combined low-dose CV-6209 (0.2 mg/kg) and PGE1 (0.8 microgram/kg/min) markedly enhanced survival and reduced MDF levels, with minimal effect when used alone.
Conclusions:
- PAF plays a significant pathophysiological role in traumatic shock.
- PAF antagonism is a promising therapeutic strategy for traumatic shock.
- Combination therapy with a PAF antagonist and PGE1 may offer synergistic benefits for treating traumatic shock.