Drug Repurposing for Schistosomiasis: Combinations of Drugs or Biomolecules

Abstract

Schistosomiasis is a major neglected tropical disease. Control of schistosomiasis currently relies on a single drug, praziquantel, and despite its efficacy against the all schistosome species that parasitize humans, it displays some problematic drawbacks and alone is ineffective in counteracting adverse pathologies associated with infection. Moreover, due to the development of the potential emergence of PZQ-resistant strains, the search for additional or alternative antischistosomal drugs have become a public health priority. The current drug discovery for schistosomiasis has been slow and uninspiring. By contrast, repurposing of existing approved drugs may offer a safe, rapid and cost-effective alternative. Combined treatment with PZQ and other drugs with different mode of action, i.e., antimalarials, shows promise results. In addition, a combination of anthelminthic drugs with antioxidant might be advantageous for modulating oxidative processes associated with schistosomiasis. Herein, we review studies dealing with combination therapies that involve PZQ and other anthelminthic drugs and/or antioxidant agents in treatment of schistosomiasis. Whereas PZQ combined with antioxidant agents might or might not interfere with anthelminthic efficacy, combinations may nonetheless ameliorate tissue damage and infection-associated complications. In fact, alone or combine with other drugs, antioxidants might be a valuable adjuvant to reduce morbidity and mortality of schistosomiasis. Therefore, attempting new combinations of anthelmintic drugs with other biomolecules such as antioxidants provides new avenues for discovery of alternatives to PZQ.

Current and Novel Therapies Against Helminthic Infections: The Potential of Antioxidants Combined with Drugs

“…In general, these treatment schedules are well tolerated with only few mild and transient adverse events as abdominal pain, dizziness, headache, nausea and urticaria [64]. Despite the efficacy against the diseases and its safety profile, PZQ presents some drawbacks, including poor solubility and an extensive metabolism via hydroxylation of the absorbed drugs to inactive metabolites [47,65]. Moreover, PZQ is inefficient against juvenile forms including the schistosomula of Schistosoma spp.…”

“…The major goals of combination chemotherapy are to minimize and/or to delay the appearance of drug resistance [90][91][92], and to achieve an additive/synergistic effect that could translate in reduced doses of drugs and/or minimized side effects [90]. Ideally for opisthorchiasis and schistosomiasis, the combined drugs would exhibit a divergent mechanism of action of PZQ and/or target the immature parasite to enhance cure and eggs reduction rates as well as pathologies associated with infection and thereby improve the chemotherapy [65].…”

“…This topic has been revised [65]. Several classes of pharmacological agents including anthelmintics, antimalarials and anti-inflammatory agents among others, have been evaluated against schistosomiasis.…”

“…Biological and natural agents as antioxidant biomolecules have attracted interest against schistosomiasis. These studies were also extensively reviewed [65]. Several antioxidants were studied, and the results are encouraging, either when administered alone or in combination with other drugs.…”

Single oral fixed-dose praziquantel-miltefosine nanocombination for effective control of experimental schistosomiasis mansoni

“…Apart from nanotechnology, drug combination therapy aiming at synergies, resistance reduction and rejuvenation of old drugs, is another approach showing increasing bene ts in the treatment of several diseases, particularly cancer [30,31] and bacterial infections [32]. In experimental schistosomiasis, promising results have been reported for combinations involving PZQ and other drugs or biomolecules, aiming at multistage targeting, amelioration of infection-associated pathologies and resistance reduction [12,14]. Despite evident advantages, combinations of free drugs may display variation in the pharmacokinetics and membrane transport among component drugs in addition to intricate dosing, resulting in inadequate outcomes [33].…”