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[Effects of anti-platelet aggregating agents on peplomycin induced pulmonary toxicity in mice]
Abstract:
In order to find a method to ameliorate pulmonary toxicity of peplomycin (PEP), microscopic changes of the lung following PEP administration and effect of anti-platelet aggregating agents on the toxicity was investigated in mice. When PEP was administered intravenously once a day for 7 days, microthrombi mainly composed of aggregated platelets and fibrin appeared in the capillaries of the lung in an early phase before severe pulmonary edematous lesions and fibrosis occurred. Combination therapy of anti-platelet aggregating agents such as phthalazinol, dipyridamole, ticlopidine and indomethacin suppressed these toxic changes. Especially, ticlopidine was the most effective and superior to prednisolone used clinically for amelioration of the toxicity. Microthrombi, preceding edematous lesions, were considered to be attributed to damages of endothelium by PEP, because PEP itself did not develop platelet aggregation in vitro and ex vivo. Therefore, the microthrombi are likely to produce congestion of pulmonary microcirculation leading to edematous lesions by increase of permeability, and to play significant roles in the development of pulmonary fibrosis in a late phase. Anti-platelet aggregating agents such as ticlopidine are concluded to ameliorate the lung toxicity by preventing microcirculation impairment with the microthrombus.
Insights
Anti-platelet agents prevent lung damage from peplomycin (PEP) by inhibiting microthrombi formation. Ticlopidine showed superior efficacy in ameliorating pulmonary toxicity in mice.
Area of Science:
- Pharmacology
- Toxicology
- Pulmonary Medicine
Context:
- Peplomycin (PEP) is an anticancer drug known to cause pulmonary toxicity.
- Pulmonary toxicity manifests as edematous lesions and fibrosis.
- The exact mechanism of PEP-induced lung injury requires further elucidation.
Purpose:
- To investigate the microscopic changes in the lungs following PEP administration in mice.
- To evaluate the efficacy of anti-platelet aggregating agents in ameliorating PEP-induced pulmonary toxicity.
- To identify potential therapeutic strategies for mitigating lung damage from PEP.
Summary:
- Intravenous administration of peplomycin (PEP) in mice led to the formation of microthrombi in lung capillaries prior to severe edematous lesions and fibrosis.
- Combination therapy with anti-platelet agents, including phthalazinol, dipyridamole, ticlopidine, and indomethacin, effectively suppressed these toxic changes.
- Ticlopidine demonstrated the most significant efficacy, outperforming the clinical drug prednisolone in ameliorating PEP-induced pulmonary toxicity.
- Microthrombi formation is hypothesized to result from endothelial damage induced by PEP, leading to pulmonary microcirculation impairment, increased permeability, and subsequent fibrosis.
Impact:
- This study identifies microthrombi as a key factor in the pathogenesis of peplomycin-induced pulmonary toxicity.
- Anti-platelet aggregating agents, particularly ticlopidine, represent a promising therapeutic approach to prevent or reduce lung damage associated with peplomycin treatment.
- Findings suggest a novel strategy for managing chemotherapy-induced lung injury, potentially improving patient outcomes.