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New pharmacological studies with pentoxifylline
W J Novick1, G Sullivan, G Mandell
1Hoechst-Roussel Pharmaceuticals Inc., Somerville, NJ.
Abstract:
Polymorphonuclear (PMN) overactivation plays a critical role in microcirculation as well as in conditions such as multiorgan failure (MOF). Pentoxifylline has been shown to prevent PMN activation by endotoxin and cytokines such as TNF alpha and IL-1. In addition, MOF induced by IL-2 in animals can be prevented by pentoxifylline. The present studies evaluated two aspects of PMN activation and pentoxifylline interaction. The first was the time sequence for pentoxifylline prevention of TNF alpha activation and the second was the activity of pentoxifylline on amphotericin B activation of PMNs. TNF alpha activation of PMNs is blocked by pentoxifylline when cells are exposed to pentoxifylline prior to TNF alpha or after TNF alpha. Amphotericin B activation of PMNs was demonstrated by a decreased chemotaxis, increased chemiluminescence, and increased PMN spreading. In all conditions, pentoxifylline decreased amphotericin B activation of PMNs. These results suggest that pentoxifylline can reverse cytokine activation of PMNs and that pentoxifylline may alter some of the toxic effects of amphotericin.
Insights
Pentoxifylline effectively blocks tumor necrosis factor alpha (TNF α) activation of polymorphonuclear cells (PMNs) and reduces amphotericin B activation. This suggests pentoxifylline may mitigate PMN overactivation and related toxic effects.
Area of Science:
- Immunology
- Pharmacology
- Critical Care Medicine
Background:
- Polymorphonuclear (PMN) overactivation contributes to microcirculation issues and multiorgan failure (MOF).
- Pentoxifylline is known to inhibit PMN activation by endotoxins and cytokines like TNF α and IL-1.
- Pentoxifylline has demonstrated protective effects against IL-2-induced MOF in animal models.
Purpose of the Study:
- To investigate the temporal relationship between pentoxifylline administration and TNF α-induced PMN activation.
- To assess the effects of pentoxifylline on PMN activation induced by amphotericin B.
Main Methods:
- Evaluating the timing of pentoxifylline's inhibitory effect on TNF α-mediated PMN activation.
- Assessing PMN activation markers (chemotaxis, chemiluminescence, spreading) following amphotericin B exposure with and without pentoxifylline.
Main Results:
- Pentoxifylline effectively blocked TNF α activation of PMNs, regardless of whether it was administered before or after TNF α.
- Pentoxifylline reduced PMN activation by amphotericin B, as evidenced by decreased chemotaxis and spreading, and altered chemiluminescence.
Conclusions:
- Pentoxifylline demonstrates the ability to reverse TNF α-induced PMN activation.
- Pentoxifylline may possess therapeutic potential in mitigating the toxic effects associated with amphotericin B-induced PMN activation.