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Abstract
Leishmaniasis is one of the diverse and neglected tropical diseases. Embryo-toxicity of drugs has always been a major concern. Chick embryo is a preclinical model relevant in the assessment of adverse effects of drugs. The current study aimed to assess embryonic histopathological disorders and amniotic fluid biochemical changes following meglumine antimoniate treatment. The alteration of vascular branching pattern in the chick’s extra-embryonic membrane and exploration of molecular cues to early embryonic vasculogenesis and angiogenesis were also quantified. Embryonated chicken eggs were treated with 75 or 150 mg/kg of meglumine antimoniate. Embryo malformations, growth retardation and haemorrhages on the external body surfaces were accompanied by histopathological lesions in the brain, kidney, liver and heart in a dose-dependent manner. Significant rise occurred in the biochemical indices of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase and amylase in the amniotic fluid. Quantification of the extra-embryonic membrane vasculature showed that the anti-angiogenic and anti-vasculogenic effects of the drug were revealed by a significant decrease in fractal dimension value and mean capillary area. The relative expression levels of vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 mRNA also significantly reduced. Concerns of a probable teratogenicity of meglumine antimoniate were established by data presented in this study. It is concluded that tissue lesions, amniotic fluid disturbance, altered early extra-embryonic vascular development and gene expression as well as the consecutive cascade of events, might eventually lead to developmental defects in embryo following meglumine antimoniate treatment. Therefore, the use of meglumine antimoniate during pregnancy should be considered as potentially embryo-toxic. Hence, physicians should be aware of such teratogenic effects and limit the use of this drug during the growing period of the fetus, particularly in rural communities. Further pharmaceutical investigations are crucial for planning future strategies.
Highlights
Leishmaniasis is a major medical and veterinary problem worldwide, affecting 12 million people in 98 countries with two million new cases each year and 350 million people at risk
This study is presented in 3 experiments: Experiment 1, where chicken eggs were treated with Meglumine antimoniate (MA) at dosages of 75 and 150 mg per kg egg-weight at day 4 of incubation
Chick embryo is a preclinical model which is relevant for the assessment of adverse effects of drugs, whereby the interventions cannot be done in human fetus due to ethical reasons, but will inspire researchers and clinicians for specific changes in the design of subsequent drug prescription in patients
Summary
Leishmaniasis is a major medical and veterinary problem worldwide, affecting 12 million people in 98 countries with two million new cases each year and 350 million people at risk. Several clinical and epidemiological forms are predominant, depending on the causative species. 22 species are responsible for various clinical forms including cutaneous, mucocutaneous, visceral, diffuse and post kala-azar dermal leishmaniasis in five continents. Most of the cases are largely hidden, concentrated in remote rural areas, and are more common in urban slums and shanty towns. The disease is largely salient, as the people affected have little political voice with low standard of living in terms of socio- economic and hygienic conditions[2]
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