Subchronic Toxicological Study of Two Artemisinin Derivatives in Dogs

Abstract

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.

A cryptic cycle in haematopoietic niches promotes initiation of malaria transmission and evasion of chemotherapy

“…Extramedullary or stress haematopoiesis can occur in many tissues, particularly in the spleen during infectious disease, as a result of hereditary blood disorders, such as β-thalassaemia 39 , 40 , or even following ART-induced haemolysis in dogs 41 . Splenomegaly is a significant and common feature of ongoing malaria infection resulting from its roles as a primary filter of parasitised erythrocytes and the seat of initial immune responses to infection, as well as parasite-induced tissue remodelling 42 .…”

Artemether-lumefantrine and liver enzyme abnormalities in non-severe Plasmodium falciparum malaria in returned travellers: a retrospective comparative study with quinine-doxycycline in a Portuguese centre

“…Hepatic (elevation of AST, ALT and GGT; liver cells degeneration on histology), cardiac, renal, and neurotoxicity, as well as embryonic malformations, associated with ACT regimens have been described in animal models [5–7, 14]. However, these have not been shown to be relevant in widespread clinical use in humans.…”

“…Hepatotoxicity associated with ACT has been described in animal models [5–7] and several series in humans have shown elevation of liver enzymes of undetermined clinical significance [8]. On the other hand, it has rarely been described for QD [9–11] and AL regimens [12].…”

Antitumor Research on Artemisinin and Its Bioactive Derivatives

“…The main obstacle of artemisnins for clinical applications was poor aqueous solubility and low bioavailability [ 136 ], leading to the requirement of high dosage of artemisnins for greater anti-tumor effects. Unfortunately, with the increasing usage of artemisnins, the side effects of them usually became more remarkable [ 151 ]. Worse still, as one kind of radical-induced therapeutic drugs, it is difficult for artemisinins to achieve local treatment [ 152 ].…”