Copper chloride and copper sulphate in combination with nitroxynil against gastrointestinal nematodes of ruminants: a possible hitchhiking synergic effect at low concentrations

Parasite infections can cause serious health problems for livestock, where infected animals show signs of anorexia, diarrhea, and hypoproteinemia (Craig, 2018). Helminth control has been based on the strategic and preventive use of anthelmintics (i.e., benzimidazoles, macrocyclic lactones, and phenolic substitutes) (Hoste and Torres-Acosta, 2011). Among the available products to control Haemonchus spp., nitroxynil (NTX) belongs to the group of phenolic substitutes (4-hydroxy-3-iodo-5-nitrobenzonitrile) being largely used in Brazil and elsewhere. Phenolic substitutes are effective against cestode, trematode, and some hematophagous nematode parasites (Corbett and Goose, 1971). As a general rule, therapeutic doses of NTX are well tolerated by cattle and sheep. Costa et al. (2018), used NTX in lambs and observed an efficacy of > 94%, reducing the mean parasite fecal egg count (FEC), as well as reducing Haemonchus spp. and Oesophagostomum spp. infection.

The intensive use of anthelmintics has increased the selection pressure of most parasite species. Therefore, improved management strategies need to be implemented to preserve efficacy and to overcome drug failure (Papaiakovou et al., 2022). Innovative therapeutic formulations must be developed, exploring the use of novel compounds in combination with existing parasiticides. Moreover, drug-drug interactions can be optimized in preclinical trials. Bortoluzzi et al. (2021) used the 50% inhibitory concentration (IC50; mg/ml) of NTX in combination with different concentrations of the essential oil of Mentha villosa and a nanoemulsion of Mentha x piperita in vitro. The authors reported a synergic effect of these combinations against Haemonchus spp. and Trichostrongylus spp., showing an increase of more than 70% in the expected efficacy of NTX and both essential oil formulations.

Copper (Cu-II) is an essential micronutrient present in the active site of some enzymes, helping them to catalyze organic oxidative reactions (Trammell et al., 2019). Copper oxide wire particles and copper oxide needles were previously tested for the control of nematode parasites of small ruminants (Banget al., 1990, Chartieret al., 2000). The objective was to demonstrate the possibility that copper given orally to animals would reduce parasite establishment and worm counts (i.e., Haemonchus contortus) (Chartier et al., 2000), treatment frequency with commercial products, and anthelmintic resistance. Different Cu-II presentations (sulphate, nitrate, and chloride) have been described as molluscicides, also being effective in controlling schistosomiasis (Borkow and Gabbay, 2009). Leal et al. (2014) determined the performance of the supplementation of sodium selenite (0.2 mg/kg, intramuscular twice) associated with copper (3.5 mg/kg, subcutaneously) in experimentally infected lambs with H. contortus. Copper and selenium supplementation promoted an increase in total protein and a decrease in parasite burden. In a similar protocol, Fausto et al. (2014) reported that copper treatment also exhibited an improvement in weight gain in lambs.

As a metallic transition element, Cu-II also plays a vital role in various physiological processes such as neurotransmission and cellular metabolism (Gaban et al., 2015). It has been also shown that Cu-II supplementation in a balanced diet can significantly improve host resilience (Knox et al., 2006; Hefnawy and Tórtora-Pérez, 2010). Although copper can initiate oxidative, cellular, and neurodegenerative damage, it is well tolerated by host species (Gaetke and Chow, 2003). One alternative would be to test the two candidates to determine their positive (additive and synergic) interaction against a potential target (Breitinger, 2012). As proposed by Rodrigues et al. (2017), the nitro (-NO2) and hydroxyl (-OH) groups should be valuable characteristics of NTX due to their electronic availability and the possibility to retain Cu-II ions by complexation.

The in vitro larval migration inhibition test (LMIT) is used to evaluate the effect of a candidate compound on parasite motility/paralysis (Demeler et al., 2010). Other in vitro techniques were also developed to determine drug efficacy, such as the egg hatch test (EHT), and the larval development test (LDT) (Fortes and Molento, 2013). In vitro tests are well aligned with the 3R (reduce, replace, and refine) principles of animal experimentation and shall be used for preclinical experiments of drug screening as supportive mechanistic studies (Beken et al., 2016). The objective of this work was to demonstrate how copper chloride (CuCl2), copper sulphate (CuSO4), and NTX, and their combination, would affect nematode parasites.

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