*Dr. T.K. Jeffers is a courtesy professor with the department of animal science at Cornell University.
NICARBAZIN is a 1:1 chemical complex of 4,4'-dinitrocarbanalide (DNC) and 2-hydroxy-4,6 dimethylpyrimidine (HDP).
Only the DNC portion of nicarbazin possesses anticoccidial activity, but when chemically complexed with HDP, the anticoccidial activity of DNC is increased tenfold on a molecular basis (Cuckler et al., 1955).
Cuckler et al. (1956) attributed the activity of DNC to the uncoupling of oxidative phosphorylation in the mitochondria of the coccidia, thus depleting energy production in the coccidia at the schizont stage of the life cycle.
Subsequently, it was shown that micron-size crystals of nicarbazin disintegrated in water to form much smaller crystals of DNC (Rogers et al., 1983). This disintegration probably occurs in the gut of the broiler chicken, leading to much greater absorption of the biologically active DNC portion of the nicarbazin complex and, in turn, resulting in the tenfold increase in anticoccidial activity.
Ionophores are produced through fermentation of Streptomyces sp. and are uniquely capable of forming lipophylic complexes with cations such as sodium and transporting these cations into and through biological membranes (Pressman, 1976).
Sporozoites of coccidia accumulate ionophores in their pellicle membrane (Smith and Strout, 1979), resulting in an influx of sodium into the sporozoite, exceeding the parasite's ability to remove it and, in turn, leading to the death of the coccidia through energy depletion and a resultant lethal osmotic imbalance (Smith and Galloway, 1983; Smith et al., 1981).
Although the ionophore anticoccidials have different chemical formulas, they all act in the same way to create a lethal osmotic imbalance within invasive stages of the coccidia through transport of cations across the pellicle membrane prior to host cell invasion (Long and Jeffers, 1982).
In studies on combinations of suboptimal levels of chemical anticoccidials and ionophores, Callender and Jeffers (1980) unexpectedly discovered that combinations of nicarbazin and ionophores exhibit synergistic anticoccidial activity.
Although nicarbazin and ionophores both exert their anticoccidial activity, albeit differently, through energy depletion in the coccidia, the exact molecular basis for the synergistic anticoccidial activity of reduced levels of the two remains unexplained.
One might speculate that since both the DNC component of nicarbazin and ionophores exert their individual anticoccidial effect against coccidia through independent roles in energy depletion, then when the two are combined even at reduced dosages, this dual aspect of energy depletion should have a synergistic anticoccidial outcome.
Extensive studies on various proportions of narasin and nicarbazin (narasin/nicarbazin) confirmed that a 1:1 ratio of reduced levels of the two components was the most appropriate in providing synergistic anticoccidial activity against all species of chicken coccidia (Callender et al., 1987; Tonkinson et al., 1987). Additional studies on the efficacy and safety of 1:1 ratios of narasin/nicarbazin resulted in the development and regulatory approval of this combination as an anticoccidial premix product for broilers.
The narasin/nicarbazin combination exhibited outstanding anticoccidial efficacy in floor-pen trials (Guneratne and Gard, 1991; Long et al., 1988; Watkins and Bafundo, 1993), and this combination has now been used extensively by global broiler producers for the prevention of coccidiosis.
Anticoccidial drug resistance problems have been encountered following commercial use of many anticoccidial drugs over the years (Chapman, 1997; Chapman and Hacker, 1994), in turn resulting in reduced broiler performance.
Bafundo and Jeffers (1990) found it difficult to develop resistance to combinations of monensin and nicarbazin through 60 generations of intentional selection in the laboratory.
Although there have been reports of a loss of sensitivity to the narasin/nicarbazin combination based on the results of short-term sensitivity evaluations in the laboratory (Bafundo et al., 2008; Tamas and Wilks, 1989; Tamas et al., 1991), such anticoccidial sensitivity tests are generally not good predictors of the performance of anticoccidial programs in the field (Jeffers, 2013; Watkins, 1997).
To date, a reduction in broiler performance due to drug resistance problems has not been well documented following the use of synergistic nicarbazin/ionophore combinations in commercial broiler production.
Aside from the synergistic anticoccidial activity of nicarbazin when combined with ionophores, there are other aspects of the narasin/nicarbazin combination that, no doubt, contribute to its effectiveness in maintaining intestinal integrity.
The narasin/nicarbazin product, established through extensive research, is the ideal ratio of the two components. In order to gain the synergistic anticoccidial benefit of a combination of nicarbazin and an ionophore, the appropriate ratio of the two must first be determined through comparative evaluation of many different ratios of the two components (Callender and Jeffers, 1980).
Furthermore, the success of the narasin/nicarbazin combination in maintaining intestinal integrity may be due, in part, to the well-documented activity of narasin against Clostridium perfringens, thus helping to prevent necrotic enteritis. Among the ionophores approved for use in broilers, narasin is perhaps the most active against C. perfringens in vitro (Watkins et al., 1997) as well as in challenge studies in broilers (Brennan et al., 2001; Collier et al., 2008).
Although nicarbazin is inactive in this regard, the presence of narasin when combined with nicarbazin continues to provide some protection against necrotic enteritis (Lanckreit et al., 2010). This property of narasin is especially valuable to broiler producers in global areas where the use of growth-promoting antibiotics is banned, such as in the European Union.
Narasin is also effective for reducing gizzard erosion and ulceration in broilers (Kaldhusdal et al., 2012). This may also be due to the activity of narasin against C. perfringens since gizzard erosion is associated with increased levels of C. perfringens in broilers (Novoa-Garrido et al., 2006).
What is interesting is that, apart from its anticoccidial activity, nicarbazin in combination with narasin has a significant positive impact on broiler pigmentation (Bafundo, 1989).
It seems likely that this benefit has contributed to the use of this combination by broiler producers, especially in broiler operations in which carcass color is an important production parameter.
In summary, several ionophores are known to be synergistic with nicarbazin as anticoccidials (Callender and Jeffers, 1980). Unfortunately, there is a general lack of scientific publications comparing the anticoccidial properties of nicarbazin in combination with different ionophores.
At present, the combination of narasin and nicarbazin is the only such combination for which there has been adequate published information available for review, which is why it was the principal subject of this article.
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