Abstract:
Background: Amodiaquine (AQ) along with sulphadoxine-pyrimethamine (SP) offers effective and cheaper
treatment against chloroquine-resistant falciparum malaria in many parts of sub-Saharan Africa. Considering the
previous history of hepatitis, agranulocytosis and neutrocytopenia associated with AQ monotherapy, it becomes
imperative to study the toxicity of co-administration of AQ and SP. In this study, toxicity and resulting global
differential gene expression was analyzed following exposure to these drugs in experimental Swiss mice.
Methods: The conventional markers of toxicity in serum, oxidative stress parameters in tissue homogenates,
histology of liver and alterations in global transcriptomic expression were evaluated to study the toxic effects of
AQ and SP in isolation and in combination.
Results: The combination therapy of AQ and SP results in more pronounced hepatotoxicity as revealed by
elevated level of serum ALT, AST with respect to their individual drug exposure regimen. Furthermore, alterations
in the activity of major antioxidant enzymes (glutathione peroxidase, superoxide dismutase, catalase, glutathione
reductase), indicating the development of oxidative stress, was more significant in AQ+SP combination therapy.
cDNA microarray results too showed considerably more perturbed gene expression following combination therapy
of AQ and SP as compared to their individual drug treatment. Moreover, a set of genes were identified whose
expression pattern can be further investigated for identifying a good biomarker for potential anti-malarial
hepatotoxicity.
Conclusion: These observations clearly indicate AQ+SP combination therapy is hepatotoxic in experimental Swiss
mice. Microarray results provide a considerable number of potential biomarkers of anti-malarial drug toxicity. These
findings hence will be useful for future drug toxicity studies, albeit implications of this study in clinical conditions
need to be monitored with cautions.
