Monensin ionophore

This experiment describes the preparation and evaluation of two liquid-membrane Na+ ion-selective electrodes, using either the sodium salt of monensin or a hemisodium ionophore as ion exchangers incorporated into a PVG matrix. Electrodes prepared using monensin performed poorly, but those prepared using hemisodium showed a linear response over a range of 0.1 M to 3 X 10 M Na+ with slopes close to the theoretical value. 

Coccidiosis is a proto2oal disease of the intestinal tract of animals that leads to severe loss of productivity and death. The development and widespread use of anticoccidials has revolutionized the poultry industry. The estimated world market for anticoccidial agents in 1989 was 425 million and this was dominated by the polyether ionophore antibiotics monensin, salinomycin [53003-10-4], n imsm [55134-13-9], la.s9locid, and maduramicin [84878-61-5] (26). 

Anticoccidial Activity. The 1968 report that claimed monensin has activity against Eimeria sp., particularly E. tenella E. macdma., and E. acervulina greatly altered the prevention and control of coccidiosis in poultry (172). It is estimated that the polyether ionophores presently constitute more than 80% of the total worldwide usage of anticoccidials (173). Lasalocid and monensin have been approved for use in control of coccidiosis in cattle. 

The total world market for the use of ionophores for feed efficiency improvement in mminants is approximately 80— 90 million. The United States is the largest market. Lasalocid and monensin are the only members of this class cleared for use. Outside the United States, salinomycin is used in limited quantities. Worldwide usage is about 1.5 million kg. 

Some of these compounds could be considered as dietary additives, but various other terms, including pesticides, can also be used. They can have beneficial effects on the environment and this aspect will be discussed later. The ionophore monensin, which is an alicyclic polyether (Figure 1), is a secondary metabolite of Streptomyces and aids the prevention of coccidiosis in poultry. Monensin is used as a growth promoter in cattle and also to decrease methane production, but it is toxic to equine animals. " Its ability to act as an ionophore is dependent on its cyclic chelating effect on metal ions. ° The hormones bovine somatotropin (BST) and porcine somatotropin (PST), both of which are polypeptides, occur naturally in lactating cattle and pigs, respectively, but can also be produced synthetically using recombinant DNA methods and administered to such animals in order to increase milk yields and lean meat production. "... 

Other mobile carrier ionophores include monensin and nonaetin (Figure 10.39). The unifying feature in all these structures is an inward orientation of polar groups (to coordinate the central ion) and outward orientation of non-... 

Chemical modification of monensin, polyether ionophoric antibiotic with bound tetrahydropyran, two tetrahydrofuran, and octahydrospiro-2,2 -furopyran fragments 97YZ583. 

Cholanic acid also possesses the ability of transporting cations across a lipophilic membrane but the selectivity is not observed because it contains no recognition sites for specific cations. In the basic region, monensin forms a lipophilic complex with Na+, which is the counter ion of the carboxylate, by taking a pseudo-cyclic structure based on the effective coordination of the polyether moiety. The lipophilic complex taken up in the liquid membrane is transferred to the active region by diffusion. In the acidic region, the sodium cation is released by the neutralization reaction. The cycle is completed by the reverse transport of the free carboxylic ionophore. 

Many other cyclic and noncyclic organic carriers with remarkable ion selectivities have been used successfiilly as active hosts of various liquid membrane electrodes. These include the 14-crown-4-ether for lithium (30) 16-crown-5 derivatives for sodium bis-benzo-18-crown-6 ether for cesium the ionophore ETH 1001 [(R,R)-AA -bisd l-ethoxycarbonyl)undecyl-A,yVl-4,5-tctramcthyl-3,6-dioxaoctancdiamide] for calcium the natural macrocyclics nonactin and monensin for ammonia and sodium (31), respectively the ionophore ETH 1117 for magnesium calixarene derivatives for sodium (32) and macrocyclic thioethers for mercury and silver (33). 

The next example, shown in Fig. 4.6a, is the amusing consequence of continually increasing the concentration of background salt (beyond its aqueous solubility—just to make the point) to the shape of log /J/pH profile for acebutolol (whose normal 0.15 M salt curve [362] is indicated by the thick line in Fig. 4.6a). The base-like (cf. Fig. 4.3a) lipophilicity curve shape at low levels of salt can become an acid-like shape (cf. Fig. 4.2a) at high levels of salt An actual example of a dramatic reversal of character is the ionophore monensin, which has a log P (in a background of Na+) 0.5 greater than logP [276,281]. 

Macrocyclic compounds with ion-chelating properties occur naturally and often function as ionophores, translocating ions across biological membranes many of these compounds are small cyclic polypeptides. Some natural carboxylic polyethers are selective for Li+ and are, therefore, ionophores for Li+. Monensin, shown in Figure Id, is a natural ionophore for Na+ but it will also complex with Li+ and it has been shown to mediate the transport of Li+ across phospholipid bilayers [21]. It has been proposed that synthetic Li+-specific ionophores have a potential role as adjuvants in lithium therapy, the aim being to reduce the amount of... 

Monensin belongs to the family of polyether ionophores. These compounds consist of a series of tetrahydrofuran and tetrahydro-pyran rings and have a carboxyl group that forms neutral salts with alkali metal cations. Their three-dimensional structure presents a lipophilic hydrocarbon exterior with the cation encircled in the oxygen-rich interior. They probably act by transporting cations through the lipid bi-layer of cell membranes, thereby preventing the concentration of potassium by the cells. Evidence for this is... 

After the marketing of monensin began, there was a rush to discover more ionophores. The second ionophore to be licensed as a coccidiostat in the U.S. was X-537A, first reported by investigators at the Nutley, NJ laboratory of Hoffmann-LaRoche in 1951 (8), 16 years prior to the announced discovery of monensin. It was their misfortune not to have tested their compounds against coc-cidia. X-537A, now named lasalocid, differs from most of the other ionophores in its ability to complex with divalent cations. 

Three broad groupings, of the antibiotic substances presently used in animal production, include (a) broad-spectrum antibiotics, including penicillins and tetracyclines, which are effective against a wide variety of pathogenic and non-pathogenic bacteria (b) several narrow-spectrum antibiotics that are not used in human medicine and. (c) the ionophore antibiotics, monensin. lasalocid and salinomycin Monensin and lasalocid are used as rumen fermentation regulators in beef cattle, and the three ionophores are used as coccidiostats in poultry production. The ionophores. which are not used in human medicine, were first introduced in the 1970 s and account for most of the increase in antibiotic usage in animal production since the 1960 s. 

Weiss and MacDonald (87) recently reviewed methods for determination of ionophore antibiotics. lonophores approved for use in animal agriculture in the U.S. are lasalocid, monensin, and salinomycin. An HPLC ( ) and GLC-MS ( ) procedure have been described for lasalocid. For other ionophores, TLC-bioautography is the preferred procedure because of lack of any useful UV absorbance. However, a few TLC colorimetric procedures have been described for monensin residues in tissues (90-92). 

Physiological studies show that monensin is a sodium ionophore (15), that induces inotropic effect on guinea pig atria (17). The polyether toxins including ciguatoxin, okadaic acid, and the recently characterized brevetoxin (5, 16) also induce inotropic effect on guinea pig atrial tissue in vitro (17). Additionally, partially purified CTX has been implicated in the depolarization of nerve cells in vitro, which can be reversed by high concentrations of Ca tetrodotoxin and saxitoxin (18). 

Monitoring for ionophore residues in eggs produced in North Ireland was also carried out in 1994 (19). Narasin, monensin, and salinomycin were detected in 1, 6, and 2 eggs, respectively, of the 161 eggs totally surveyed. In all cases, the concentrations detected were less than 2.5 ppb. 

The use of amprolium (58) at 125 p.p.m. in feed soon failed to give complete control of some Eimeria species. The closely related quinoline compounds, buquinolate (60) and decoquinolate (61), and the pyridine, clopidol (62), were introduced as replacement for amprolium (58). However, all the compounds have been beset by resistance problems and today the prophylactic treatment of coccidiosis is heavily dependent upon the sodium ionophore monensin (63). 

The advent of the polyether antibiotics with the challenging aspect of stereocontrolled construction of the substituted tetrahydrofuran units has greatly extended the chemistry of this oxygen heterocycle. The nonactins (194), lasalocid A (195) and monensin (196) are among the ionophores for which syntheses have been achieved. Detailed reviews on synthesis of reduced furans are available (65HOU(6/3)l, 80H(14)1825). 

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