An effective antidotal combination of polymyxin B and methylprednisolone for α-amanitin intoxication

Area of Science:

• Toxicology
• Pharmacology
• Hepatology
• Nephrology

Background:

• Amanita phalloides mushrooms contain α-amanitin, a potent toxin causing fatal liver and kidney failure by inhibiting RNA polymerase II.
• Previous treatments with polymyxin B (polB) showed partial efficacy against α-amanitin toxicity, failing to ensure full survival or prevent inflammation.
• α-Amanitin utilizes OATP1B3 and NTCP transporters, suggesting these pathways as therapeutic targets.

Purpose of the Study:

• To evaluate the efficacy of a combined therapy of polymyxin B (polB) and methylprednisolone (MP) in fully reversing α-amanitin-induced toxicity in mice.
• To assess the protective effects of the polB + MP combination against α-amanitin-induced organ damage, inflammation, and mortality.

Main Methods:

• CD-1 mice were administered α-amanitin (0.33 mg/kg, i.p.) followed 4 hours later by a combination of polB (2.5 mg/kg, i.p.) and MP (10 mg/kg, i.p.).
• Survival rates, hepatic and renal necrosis, plasma aminotransferase levels, renal myeloperoxidase activity, and inflammatory cell infiltration were assessed.

Main Results:

• The polB + MP combination therapy resulted in 100% survival of mice intoxicated with α-amanitin.
• Significant reduction in renal and hepatic necrosis was observed in the treated group.
• The combination decreased plasma aminotransferase levels, reduced renal myeloperoxidase activity, and mitigated renal inflammatory cell infiltrate, but did not prevent hepatic inflammation.

Conclusions:

• The combination of polymyxin B and methylprednisolone represents a highly effective therapeutic strategy against α-amanitin poisoning.
• This combined treatment fully protects against mortality and significantly attenuates organ damage and renal inflammation.
• Further investigation into this therapeutic approach is warranted for clinical application in mushroom poisoning cases.