As clinicians are well aware, Chagas disease has very few treatment options. As such, recently, computer-driven drug repositioning has led to the discovery of the trypanocidal effects of clofazimine and benidipine. These compounds showed inhibitory effects on cruzipaine, the major cysteine protease of T. cruzi, in different stages of the parasite and in a mouse model of acute Chagas disease. In a mouse model of chronic Chagas disease, benidipine and clofazimine were able to reduce the parasitic load in the heart and skeletal muscles of chronically infected mice, compared to untreated mice, as well as to decrease the inflammatory process in these tissues. Further studies should be carried out to investigate synergism with benznidazole and nifurtimox in view of combination therapies. The interesting point is that clofazimine is an old antiparasitic drug developed in the 1950s, of which practically all the pharmacology is known and is clinically in use.
A 2017 study found that T cruzi, like Leishmania or the leishmaniasis parasite, is dependent on polyamines and amino acids to feed and replicate. This phenomenon was interfered with by retinol acetate, a derivative of vitamin A used in various clinical applications. Suspecting a similar action on the trypanosome, an Argentine team found that the derivative effective on this parasite was isotretinoin, which is commonly used for acne. The drug blocks the parasite’s nutrient membrane transporters and first induces shrinkage and then death by apoptosis, a mode very similar to animal cells. Isotretinoin, therefore, is a promising trypanocidal drug as it is a multi-target inhibitor of essential metabolite transporters, as well as being an approved and widely used drug in humans, which could significantly reduce the time for its possible application.
It was in 2018 that the same Argentine team discovered that another potential inhibitor of Trypanosmoma cruzi is present among clinically approved drugs, cisapride. This drug, which is a prokinetic used in digestive functional disorders It is used to treat the symptoms of gastric reflux, as it promotes the release of acetylcholine from the stomach, facilitating emptying towards digestion. The team proved that cisapride is a selective inhibitor of the transporter TcPAT12, which is necessary for the parasite to uptake polyamines for its growth. An independent Brazilian team, on the other hand, has proven that atorvastatin alone is already effective in killing the circulating forms of the parasite (tripomastigotes) but not those hidden inside cells. The drug, well known for its use against high cholesterol, is also synergistic with benznidazole and could be used safely as its pharmacology is well known and explored.
And who expected that even common antibiotics used exclusively against bacteria could also act on the trypanosome? This parasite has a cell membrane similarly composed to mammalian cells, free of peptide-glycan (such as Gram-positive bacteria) or lipo-polysaccharide (in Gram-negative bacteria). So how do antibiotics of the cephalosporin class like flucloxacillin, piperacillin (the active ingredient of Tazocin) and cefoperazone to be effective against the replication of the parasite, even better than benznidazole, the primary anti-chagas drug? These three antibiotics were found to be inhibitors of cruzipaine and 50% more effective than nifurtimox and benznidazole, in a computerized screening undertaken to reposition approved drugs and dedicate them to Chagas disease. There are no clinical studies yet, but given the current wide clinical use of these molecules, it won’t be long before their effects are tested.
A last interesting study from last August investigated the effects of ivermectin. This is a robust anti-parasite drug with an excellent tolerance and safety profile. It has historically been the drug of choice for global elimination programs of onchocerciasis and lymphatic filariasis. The molecule is an oral insecticide and is a standard treatment against intestinal helminths and ectoparasites. Experts are keen to reposition it against Chagas disease as the current humanitarian crisis in Venezuela is a regional public health threat that requires immediate action. Furthermore, in this country, leishmaniasis and the current COVID-19 are plaguing the country. Reuse of this multipurpose drug would represent a timely therapeutic approach to help mitigate the enormous burden of nationally forgotten tropical diseases. Not just academic theory, therefore, but real practical needs.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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