The objective of our study was to profile and compare the systematic changes between orally administered artesunate and intramuscularly injected artemether at a low dose over a 3-month period (92 consecutive days) in dogs. Intramuscular administration of 6 mg kg-1 artemether induced a decreased red blood cell (RBC) count (anemia), concurrent extramedullary hematopoiesis in the spleen and inhibition of erythropoiesis in the bone marrow. We also observed a prolonged QT interval and neuropathic changes in the central nervous system, which demonstrated the cortex and motor neuron vulnerability, but no behavioral changes. Following treatment with artesunate, we observed a decreased heart rate, which was most likely due to cardiac conduction system damage, as well as a deceased RBC count, extramedullary hematopoiesis in the spleen and inhibition of erythropoiesis in the bone marrow. However, in contrast to treatment with artemether, neurotoxicity was not observed following treatment with artesunate. In addition, ultra-structural examination by transmission electron microscopy showed mitochondrial damage following treatment with artesunate. These findings demonstrated the spectrum of toxic changes that result upon treatment with artesunate and artemether and show that the prolonged administration of low doses of these derivatives result in diverse toxicity profiles.

Podophyllotoxin (POD), a natural lignan distributed in podophyllum species, possesses significant antitumor and antiviral activities. But POD often causes serious side effects, such as myelosuppression, gastrointestinal toxicity, neurotoxicity, hepatic and renal dysfunction, and even death, which not only hinder its clinical application but also threaten the patient's health. Therefore, an effective treatment against POD-induced toxicity is important. Our preliminary study found that the total saponins from the stems and leaves of Panax quinquefolius L. (PQS) could significantly reduce the death of mice caused by POD. To reveal how PQS can alleviate PODinduced toxicity, further study was needed. Peripheral blood cell analysis, diarrhea score, and histological examination demonstrated that PQS could relieve myelosuppression and gastrointestinal side effects induced by POD. Then, metabolomics was performed to investigate the possible protective mechanism of PQS on POD-induced myelosuppression and gastrointestinal toxicity. Metabolomics analysis showed that metabolic changes caused by POD could be reversed by PQS to some extent; 23 metabolites altered significantly after POD exposure, and 11 metabolites significantly reversed by PQS pretreatment. Metabolic pathway analysis suggested that PQS might exhibit its protective effects by rebalancing disordered arginine, glutamine, and unsaturated fatty acid metabolism.