Inhibition of biological effects of endotoxins by phenothiazines

Area of Science:

• Biochemistry
• Pharmacology
• Immunology

Background:

• Endotoxins from bacteria trigger significant immune responses, including hypotension and the release of cytokines like tumor necrosis factor (TNF).
• Phenothiazines are a class of drugs with diverse pharmacological activities, and their interactions with bacterial endotoxins and endotoxin-induced mediators were not fully understood.

Purpose of the Study:

• To investigate the interactions between bacterial endotoxins and various phenothiazine derivatives.
• To examine the role of these interactions in modulating endotoxin-induced hypotension and TNF production both in vitro and in vivo.

Main Methods:

• Spectrophotometric methods were employed to measure complex formation between endotoxins and compounds like phenothiazines, benzodiazepines, amantadine, and promethazine.
• In vivo studies involved assessing endotoxin-induced hypotension in dogs pretreated with phenothiazines.
• In vitro and in vivo experiments evaluated the effect of promethazine on endotoxin-induced TNF production in human monocytes and animal models.

Main Results:

• Complex formation was observed between endotoxins and several tested compounds, including phenothiazines and promethazine.
• Phenothiazine pretreatment prevented endotoxin-induced hypotension in dogs, but the endotoxin-phenothiazine complex retained its hypotensive activity.
• Promethazine effectively prevented both in vitro and in vivo TNF induction by endotoxins.

Conclusions:

• Phenothiazines, particularly promethazine, exhibit protective effects against endotoxin-induced hypotension and TNF release.
• The mechanism of protection appears to involve inhibition of TNF induction rather than direct neutralization of endotoxin activity through complex formation.
• These findings highlight the potential of specific phenothiazines in managing endotoxemia-related complications.