monensin and salinomycin

Chemotherapy is one of the standard methods for the treatment of malignant tumors. It aims to cause lethal damage to cellular structures, mainly DNA. Noteworthy, in recent years discoveries of novel anticancer agents from well-known antibiotics have opened up new treatment pathways for several cancer diseases. The aim of this review article is to describe new applications for the following antibiotics: doxycycline (DOX), salinomycin (SAL), monensin (MON) and ivermectin (IVR) as they are known to show anti-tumor activity, but have not yet been introduced into standard oncological therapy. To date, these agents have been used for the treatment of a broad-spectrum of bacterial and parasitic infectious diseases and are widely available, which is why they were selected. The data presented here clearly show that the antibiotics mentioned above should be recognised in the near future as novel agents able to eradicate cancer cells and cancer stem cells (CSCs) across several cancer types.

Topics: Antineoplastic Agents; Doxycycline; Humans; Ivermectin; Monensin; Neoplasms; Pyrans

Topics: Anti-Bacterial Agents; Ethers; Furans; Genes, Bacterial; Monensin; Multienzyme Complexes; Open Reading Frames; Pyrans; Streptomyces

The current study describes the pharmacokinetic parameters of two carboxylic polyether ionophores: monensin in turkeys and salinomycin in chickens. These data can be used to understand and predict the occurrence of undesirable residues of coccidiostats in edible tissues of these animal species. Special attention is paid to the distribution of residues between the different edible tissues during and at the end of the treatment period. For the bioavailability studies, monensin was administered to turkeys intravenously, in the left wing vein, at a dose of 0.4 mg /kg and orally at a dose of 20 mg /kg. Salinomycin was administered to chickens intravenously, in the left wing vein, at a dose of 0.25 mg /kg and orally at a dose of 2.5 mg /kg. Residue studies were carried out with supplemented feed at the rate of 100 mg /kg of feed for monensin in turkeys and 70 mg /kg for salinomycin in chickens, respectively. Coccidiostats had a low bioavailability in poultry (around 30% for monensin in chickens, around 1% for monensin in turkeys and around 15% for salinomycin in chickens). Monensin in chickens had a longer terminal half-life (between 3.07 and 5.55 h) than both monensin in turkeys (between 1.36 and 1.55 h) and salinomycin in chickens (between 1.33 and 1.79 h). The tissue /plasma partition coefficients showed a higher affinity of both monensin and salinomycin for fat, followed by liver and muscle tissue. The depletion data showed a fairly rapid elimination of coccidiostats in all the tissues after cessation of treatment. According to the results of depletion studies, a withdrawal period of 1 day seems sufficient to avoid undesirable exposure of consumers.

Topics: Adipose Tissue; Administration, Oral; Animals; Area Under Curve; Biological Availability; Chickens; Coccidiostats; Female; Half-Life; Liver; Male; Monensin; Muscle, Skeletal; Pyrans; Tissue Distribution; Turkeys

Anticoccidial vaccine and an anticoccidial drug rotation program were compared to determine which program was more effective in producing coccidia populations sensitive of 1 ppm diclazuril. The study used an anticoccidial drug-sensitivity battery test (AST) to determine the baseline level of diclazuril sensitivity to field isolates of Eimeria spp. from seven broiler complexes that had used diclazuril. Based on percentage reduction in weight gain and lesion scores, 25% or fewer of the isolates were effectively controlled by diclazuril. Following the baseline sampling, four of the complexes switched to a nondiclazuril in-feed anticoccidial drug program and three of the complexes switched to a vaccination program for two broiler grow-out cycles as the sole coccidiosis-control program. This study demonstrated that the vaccine used (Coccivac-B) contained anticoccidial drug-sensitive strains. Eimeria isolates were subsequently collected from the identical houses and diclazuril AST results were compared with the baseline AST results. Following the two grow-out cycles, sensitivity of the isolates to diclazuril from the four complexes that continued to use in-feed anticoccidial drugs remained essentially unchanged. The isolates from the three complexes that switched to the vaccination program demonstrated a marked increase in diclazuril sensitivity, with 60%-100% of the isolates from each complex effectively controlled by diclazuril. Vaccination with the anticoccidial drug-sensitive strains produced a measurable increase in the level of sensitivity to diclazuril.

Topics: Animals; Chickens; Coccidiosis; Coccidiostats; Drug Resistance; Eimeria; Male; Monensin; Nicarbazin; Nitriles; Poultry Diseases; Protozoan Vaccines; Pyrans; Triazines

The effect of continuous in-feed administration of anticoccidial agents on antimicrobial sensitivity and the level of bacterial shedding in poultry experimentally infected with Salmonella enterica subsp. enterica serotype Typhimurium definitive type 104 (DT104) were investigated. On day 0, 1,200 1-day-old Salmonella-free broiler chicks were placed into 50 pens, and the pens were randomly allocated to one of five treatments: nonsupplemented (negative control; T1), monensin at 120 mg/kg of diet (T2), salinomycin at 60 mg/kg of diet (T3), semduramicin at 20 mg/kg of diet (T4), or semduramicin at 25 mg/kg of diet (T5). Each bird was inoculated with a well-characterized strain of serotype Typhimurium DT104 on day 10. On day 49, the birds were euthanatized humanely. Bulk fecal samples were collected on days 13, 43, and 48 and were examined for organisms which had acquired resistance. The genetic basis of acquired resistance was determined from representative samples of isolates. Of 784 Salmonella-selective plates supplemented with antimicrobial agents, only 33 showed growth. These isolates came from all treatment regimens, including the nonsupplemented control. A number of phenotypic changes were observed; these included changes in motility, phage type, and agglutination properties. Supplementation of the diet with an anticoccidial drug does not appear to affect antimicrobial resistance or the level of excretion of salmonellae. Most of the changes observed do not seem to be related to the presence of a supplement in feed. Salmonellae appear to be capable of acquiring antimicrobial resistance and phenotypic changes independently of specific antimicrobial selection pressures.

Topics: Animal Feed; Animals; Anti-Bacterial Agents; Chickens; Dietary Supplements; Feces; Genotype; Intestinal Mucosa; Monensin; Nigericin; Phenotype; Pyrans; Salmonella Infections, Animal; Salmonella typhimurium

Three experiments (Exp.) were conducted to determine the interactive effects of sodium bentonite (NaB) with the efficacy of monensin (MON) or salinomycin (SAL) in coccidiosis-infected chicks. Male broiler chicks 5 to 14 d of age were used, and each treatment was replicated with eight (Exp. 1) or four (Exp. 2 and 3) pens of five chicks each. In Exp. 1, MON (80 ppm), NaB (0.50%), or MON+NaB were fed to uninfected and coccidiosis-infected (5 x 10(5) sporulated Eimeria acervulina oocysts on Day 2 of the Exp.) chicks in a 2 x 2 x 2 factorial arrangement of treatments. Experiment 2 was identical to Exp. 1, but SAL (30 ppm) replaced MON as the anticoccidial additive. In Exp. 3, MON (55 ppm) or SAL (22 ppm) were added individually or with NaB (0.50%) to diets for uninfected or coccidiosis-infected chicks. Coccidial infection reduced (P < 0.01) gain, feed intake, gain:feed, plasma carotenoids, and percentage tibia ash in all experiments. The MON and SAL additions increased these response criteria in infected chicks (coccidiosis by anticoccidial, P < 0.07), except MON did not increase (P > 0.10) feed intake or tibia ash in Exp. 3. In Exp. 3, NaB partially reduced the positive effect of MON on daily gain (NaB by MON, P < 0.03), and of SAL on feed intake (NaB by SAL, P < 0.08). The NaB addition also increased gain:feed (P < 0.08), and the increase was greater in infected chicks (coccidiosis by NaB, P < 0.08). Also in Exp. 3, SAL increased feed intake more in chicks not fed NaB than in chicks fed NaB (SAL by NaB, P < 0.08). Dietary NaB (0.5%) may reduce the efficacy of MON and SAL in coccidiosis-infected chicks when these additives are added at less than recommended levels.

Topics: Animals; Bentonite; Carotenoids; Chickens; Coccidiosis; Coccidiostats; Diet; Drug Interactions; Eating; Male; Monensin; Poultry Diseases; Pyrans; Tibia; Weight Gain

The master transcriptional regulator MYB is a key oncogenic driver in several human neoplasms, particularly in acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). MYB is therefore an attractive target for drug development in MYB-activated malignancies. Here, we employed a MYB-reporter cell line and identified the polyether ionophores monensin, salinomycin, and nigericin as novel inhibitors of MYB activity. As a proof of principle, we show that monensin affects the expression of a significant number of MYB-regulated genes in AML cells and causes down-regulation of MYB expression, loss of cell viability, and induction of differentiation and apoptosis. Furthermore, monensin significantly inhibits proliferation of primary murine AML cells but not of normal hematopoietic progenitors, reflecting a high MYB-dependence of leukemic cells and underscoring the efficacy of monensin in MYB-activated malignancies. Importantly, monensin also suppressed the viability and non-adherent growth of adenoid cystic carcinoma (ACC) cells expressing MYB-NFIB fusion oncoproteins. Our data show that a single compound with significant MYB-inhibitory activity is effective against malignant cells from two distinct MYB-driven human neoplasms. Hence, monensin and related compounds are promising molecular scaffolds for development of novel MYB inhibitors.

Topics: Animals; Carcinoma, Adenoid Cystic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Mice; Monensin; Nigericin; Proteolysis; Proto-Oncogene Proteins c-myb; Pyrans; THP-1 Cells

Topics: Animals; Chickens; Chromatography, Liquid; Coccidiosis; Eggs; Food Analysis; Humans; Lactones; Lasalocid; Liquid-Liquid Extraction; Monensin; Nigericin; Piperidines; Poultry; Pyrans; Quinazolinones; Robenidine; Tandem Mass Spectrometry; United States; United States Food and Drug Administration

An analytical method was developed and validated for the determination of three polyether ionophores (monensin, lasalocid, and salinomycin) in 60 samples of Brazilian Minas Frescal cheese by UHPLC-MS/MS. Linearity ranged from 1 to 8 μg kg

Topics: Brazil; Cheese; Chromatography, High Pressure Liquid; Food Contamination; Ionophores; Lasalocid; Monensin; Pyrans; Tandem Mass Spectrometry

Topics: Antineoplastic Agents; Betulinic Acid; Cell Line, Tumor; Cell Proliferation; Cell Survival; Ethers; Humans; Ionophores; Lasalocid; Molecular Structure; Monensin; Pentacyclic Triterpenes; Polymerization; Pyrans

Ionophore antimicrobials are heavily used in the livestock industries, both for preventing animal infection by coccidia protozoa and for increasing feed efficiency. Ionophores are excreted mostly unmetabolized and are released into the environment when manure is land-applied to fertilize croplands. Here, an analytical method was optimized to study the occurrences of five ionophore residues (monensin, lasalocid, maduramycin, salinomycin, and narasin) in dairy manure after solid-liquid separation and further treatment of the liquid manure by a membrane-based treatment system. Ionophore residues from the separated solid manure (dewatered manure) and suspended solids of manure slurry samples were extracted using ultrasonication with methanol, followed by sample clean-up using solid phase extraction (SPE) and subsequent analysis via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The use of an ethyl acetate and methanol (1:1 v:v) mixture as an SPE eluent resulted in higher recoveries and lower method quantitation limits (MQL), when compared to using methanol. Overall recoveries from separated solid manure ranged from 73 to 134%. Liquid manure fractions were diluted with Nanopure™ water and cleaned up using SPE, where recoveries ranged from 51 to 100%. The developed extraction and LC-MS/MS methods were applied to analyze dairy manure samples subjected to an advanced manure treatment process involving a membrane-based filtration step (reverse osmosis). Monensin and lasalocid were detected at higher concentrations in the suspended solid fractions (4.40-420 ng/g for lasalocid and 85-1950 ng/g for monensin) compared to the liquid fractions (

Topics: Animals; Anti-Infective Agents; Cattle; Chromatography, Liquid; Coccidia; Coccidiosis; Ionophores; Lactones; Lasalocid; Manure; Methanol; Monensin; Pyrans; Solid Phase Extraction; Tandem Mass Spectrometry

Salinomycin (SAL) and monensin (MON) are polyether ionophore antibiotics commonly used in veterinary medicine. They are known from their anti-cancer activity against various types of cancer cells, including those that display multi-drug resistance as well as cancer stem cells. In order to increase the biological activity profile and reduce toxicity against normal cells, while retaining the activities in the micromolar range, a library of ester and amide derivatives of SAL was synthesized and previously reported. In this paper, we examined the activity of SAL, its ten derivatives, and MON on primary acute lymphoblastic leukemia cells. MON and six SAL derivatives were more potent than SAL in cell viability assays. Further, selected active SAL analogs induced characteristics of apoptotic cell death and increased expression of p53. Moreover, SAL acted synergistically with the Bcl-2 inhibitor ABT-263, whereas 2,2,2-trifluoroethyl ester, the most active analog of SAL, antagonized ABT-263, suggesting possible differences in molecular mechanism.

Topics: Amides; Aniline Compounds; Cell Line, Tumor; Cell Proliferation; DNA Fragmentation; Esters; Humans; Monensin; Poly(ADP-ribose) Polymerases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-bcl-2; Pyrans; Sulfonamides; Tumor Suppressor Protein p53

Cadmium (Cd) is an environmental pollutant shown to induce multi organ dysfunction. In this study we present novel data about the effects of meso-2,3-dimercaptosuccinic acid (DMSA), monensin and salinomycin on the concentration of Cd in skeletal muscles of mice exposed to Cd (II) acetate treatment for 14 days. The impact of Cd and the chelating agents on the endogenous concentrations of calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), phosphorous (P), selenium (Se) and zinc (Zn) was also investigated. Subacute exposure of mice to Cd (II) acetate resulted in a significant accumulation of the toxic metal ion in the skeletal muscles compared to the untreated controls. Salinomycin most effectively mobilized Cd from the muscles compared to DMSA and monensin. The Cd exposure and the tested chelating agents did not significantly alter the endogenous concentrations of the selected essential elements in mouse muscles. The presented results confirmed that among the tested chelating agents salinomycin is superior as a potential antidote to Cd poisoning.

Topics: Animals; Cadmium; Calcium; Chelating Agents; Copper; Homeostasis; Iron; Magnesium; Mice; Monensin; Muscle, Skeletal; Pyrans; Selenium; Succimer; Zinc

Topics: Animals; Anti-Bacterial Agents; Biofilms; Cattle; Female; Gram-Positive Bacteria; Ionophores; Lasalocid; Mastitis, Bovine; Microbial Sensitivity Tests; Monensin; Pyrans; Staphylococcal Infections; Staphylococcus; Streptococcal Infections; Streptococcus

The aim of this study was to investigate the effect of dietary supplementation with nisin alone or in combination with salinomycin or monensin on broiler chickens in terms of growth performance, selected blood parameters, digestive enzyme activity, apparent nutrient digestibility, and tibiotarsus mineralization, as well as selected gastrointestinal tract (GIT) organ weights, intestinal length, and central immune organ weights. Two independent experiments, each including 400 one-day-old female Ross 308 chicks differing in ionophore coccidiostats, i.e., salinomycin and monensin supplementation, were conducted. The following treatments were applied: experiment 1: NA-no additives, SAL-salinomycin (60 mg/kg diet), NIS-nisin (2,700 IU/kg diet), SAL+NIS-salinomycin (60 mg/kg diet) and nisin (2,700 IU/kg diet); experiment 2: NA-no additives, MON-monensin (100 mg/kg diet), NIS-nisin (2,700 IU/kg diet) and MON+NIS-monensin (100 mg/kg diet) and nisin (2,700 IU/kg diet). The addition of nisin with or without ionophores to the birds' diet improved broiler growth performance in terms of BWG and FCR (days 1 to 14) and BWG and FI (15 to 35 d; 1 to 35 d). Salinomycin showed effects similar to those of nisin influence on growth performance (1 to 35 d), while monensin supplementation resulted in lower BWG. Moreover, no additive effect between nisin and ionophores was observed. Nisin and salinomycin had no influence on the serum concentration of selected hormones and other blood biochemical parameters except glucose, which was reduced by nisin. A decrease in lipase activity was observed during nisin and salinomycin supplementation, while the apparent ileal digestibility of fat was not affected. However, the digestibility of crude protein increased with nisin administration. Additionally, the effects of nisin on decreasing the weight and length of GIT segments were observed. Supplementation with nisin and monensin was not associated with a negative impact on tibiotarsus mineralization and the immune organ index. This study suggests that nisin may be used in broiler nutrition as a growth promotor, with no negative influence on the bird's metabolism or immune status.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Chickens; Coccidiostats; Diet; Dietary Supplements; Digestion; Female; Monensin; Nisin; Pyrans; Random Allocation

Camels bear unique genotypes and phenotypes for adaptation of their harsh environment. They have unique visual systems, sniffing, water metabolism, and heat-control mechanisms that are different from other creatures. The recent announcement for the complete sequence of camel genome will allow for the discovery of many secrets of camel life. In this context, the genetic bases of camel drug-metabolizing enzymes are still unknown. Furthermore, the genomic content of camel that rendered it highly susceptible to some drugs (as monensin and salinomycin) and became easily intoxicated needs to be investigated. The objectives of this work are the annotation of camel genome and retrieval of camel for cytochrome P450 (CYP) 1A1, 2C, and 3A enzymes. This is followed by comprehensive phylogenetic, evolution, molecular modeling, and docking studies. In comparison with the human enzymes, camel CYPs showed lower evolution rate, especially CYP1A1. Furthermore, the binding of monensin, salinomycin, alfa-naphthoflavone, felodepine, and ritonavir was weaker in camel enzymes. Interestingly, rerank score indicated instable binding of monensin and salinomycin with camel CYP1A1 as well as salinomycin with camel CYP2C. The results of this work suggest that camels are more susceptible to toxicity with compounds undergoing metabolic oxidation. This conclusion was based on lower evolution rate and lower binding potency of camels compared with the human enzymes.

Topics: Animals; Camelus; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System; Genome; Humans; Inactivation, Metabolic; Molecular Sequence Annotation; Monensin; Pyrans; Water

In this study, we present a comparative assessment of the effects of two polyether ionophorous antibiotics (monensin and salinomycin) on the concentrations of lead (Pb), cooper (Cu), zinc (Zn) and iron (Fe) in the kidneys, spleen, liver and brain of Pb-intoxicated animals. Our data demonstrated that the intoxication of ICR male mice with Pb salt resulted in a significant accumulation of Pb in all studied organs of the mice compared to the untreated control animals. The biodistribution of the toxic metal was in the order kidneys>spleen>liver>brain. The treatment of the Pb-intoxicated animals with tetraethylammonium salts of monensic and salinomycinic acids significantly decreased the concentration of the toxic metal ion compared to the toxic control. The effect varied in the interval 38% (for kidneys) to 52% (for brain) compared to the toxic control group (Pb). The tetraethylammonium salt of salinomycinic acid was more effective in reducing the Pb concentration in the brain of the Pb-treated mice compared to monensin. Pb-intoxication did not affect significantly the Zn endogenous concentration compared to the normal values. The treatment of ICR male mice with Pb-salt decreased the Cu concentration in the spleen and increased the Cu concentration in the liver compared to the untreated control animals. The detoxification of the Pb-intoxicated mice with tetraethylammonium salts of salinomycinic and monensic acids restored the Cu concentration in the spleen, but did not affect the Cu levels in the liver. The Pb-intoxication of the ICR mice resulted in a significant decrease of the Fe-concentration in the spleen and liver compared to the untreated control animals. The administration of the tetraethylammonium salts of salinomycinic and monensic acids to the Pb-treated animals restored the levels of Fe in both organs.

Topics: Animals; Ions; Iron; Lead; Lead Poisoning; Liver; Male; Mice, Inbred ICR; Monensin; Pyrans; Salts; Spleen; Tissue Distribution

Monensin (MON) and salinomycin (SAL), known as polyether ionophore antibiotics (IPAs), are extensively used in livestock industry and can enter the environment via animal manure and agricultural runoff. Although some studies have investigated the environmental fate and transformation of IPAs, the lack of information on IPAs' aqueous-phase chemical properties is a major hindrance for further in-depth research. This study was able to experimentally determine the acidity constants (pKa), metal-complex dissociation constants (Kdiss), and intrinsic aqueous solubility of MON species, and some of these properties of SAL. The pKa value of MON was found to be 4.5, close to other aliphatic carboxylic acids and the predicted value by the computer program ChemAxon. The metal-complex dissociation constants of MON were estimated to be 0.058 and 0.573 with sodium ion (Na(+)) and potassium ion (K(+)), respectively. The Kdiss value of SAL with sodium ion was found to be 1.31. Compared to the previous values determined in organic solvents, the Kdiss of MON in aqueous phase are several orders of magnitude higher but maintain the same relative selectivity toward metal ions (Na(+) versus K(+)). The determined pKa and Kdiss values were also used to assess the aqueous solubility limits of different IPA species under different pH and metal ion concentrations. Results from this study provide more accurate information for the properties of IPAs. The obtained constants can be applied to predict the speciation of IPAs in various aquatic systems and help shed light on the environmental fate of IPAs.

Topics: Anti-Bacterial Agents; Ionophores; Molecular Structure; Monensin; Pyrans

African trypanosomes are the causative agents of sleeping sickness in humans and nagana disease in livestock animals. As the few drugs available for treatment of the diseases have limited efficacy and produce adverse reactions, new and better tolerated therapies are required. Polyether ionophores have been shown to display anti-cancer, anti-microbial and anti-parasitic activity. In this study, derivatives of the polyether ionophores, salinomycin and monensin were tested for their in vitro activity against bloodstream forms of Trypanosoma brucei and human HL-60 cells.. Most polyether ionophore derivatives were less trypanocidal than their corresponding parent compounds. However, two salinomycin derivatives (salinomycin n-butyl amide and salinomycin 2,2,2-trifluoroethyl ester) were identified that showed increased anti-trypanosomal activity with 50 % growth inhibition values in the mid nanomolar range and minimum inhibitory concentrations of below 1 μM similar to suramin, a drug used in the treatment of sleeping sickness. In contrast, human HL-60 cells were considerably less sensitive towards all polyether ionophore derivatives. The cytotoxic to trypanocidal activity ratio (selectivity) of the two promising compounds was greater than 250.. The data indicate that polyether ionophore derivatives are interesting lead compounds for rational anti-trypanosomal drug development.

Topics: HL-60 Cells; Humans; Monensin; Parasitic Sensitivity Tests; Pyrans; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African

For the first time, a series of tertiary amides of polyether antibiotic-Salinomycin have been obtained and screened for their antibacterial activity against different strains of bacteria, including Bacillus anthracis and clinical methicillin-resistant Staphylococcus epidermidis (MRSE). Moreover, biofilm inhibition of MRSE and genotoxicity tests against Bacillus subtilis have been performed. Our studies show that Salinomycin and its some derivatives are active against tested bacteria and exhibited definitely bacteriostatic, not bactericidal activity.

Topics: Amides; Anti-Bacterial Agents; Bacillus anthracis; Biofilms; Drug Resistance, Bacterial; Pyrans; Staphylococcus epidermidis

The cytotoxic effect of monensin, narasin and salinomycin followed by their co-action with silybin in the cell line cultures of human hepatoma (HepG2), chicken hepatoma (LMH) or rat myoblasts (L6) have been investigated. The effective concentration of the studied ionophoric polyethers has been assessed within two biochemical endpoints: mitochondrial activity (MTT assay) and membrane integrity (LDH assay) after 24h incubation of each compound and farther, the cytotoxicity influenced in course of their interaction with silybin was determined. The most affected endpoints were found for inhibition of mitochondrial activity of the hepatoma cell lines and their viability depended on concentration of the ionophoric polyether, as well as on the cell line tested. The rat myoblasts were more sensitive target for cellular membrane damage when compared to inhibition of mitochondrial activity. An interaction between the ionophoric polyethers and silybin resulted a considerable cytotoxicity decrease within all studied cell lines; the combination index (CI) showed differences of interaction mode and dependence on cell culture, concentration of silybin, as well as the assay used. The obtained results are of interest in respect to recent findings on applicability of salinomycin and monensin for human therapy.

Topics: Animals; Cell Line; Cell Line, Tumor; Cell Survival; Chickens; Drug Interactions; Hep G2 Cells; Humans; Monensin; Myoblasts; Pyrans; Rats; Silybin; Silymarin

A series of eight new conjugates of salinomycin or monensin and Cinchona alkaloids were obtained by the Cu(I)-catalysed 1,3-dipolar Huisgen cycloaddition (click chemistry) of respective N-propargyl amides of salinomycin or monensin with four different Cinchona alkaloid derived azides. In vitro antiproliferative activity of these conjugates evaluated against three cancer cell lines (LoVo, LoVo/DX, HepG2) showed that four of the compounds exhibited high antiproliferative activity (IC50 below 3.00 μm) and appeared to be less toxic and more selective against normal cells than two standard anticancer drugs.

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cinchona Alkaloids; Click Chemistry; Humans; Monensin; Neoplasms; Pyrans

The drug target profile proposed by the Medicines for Malaria Venture for a malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of Plasmodium, thus with both curative and transmission-blocking activities. The aim of the present work was to investigate whether the class of monovalent ionophores, which includes drugs used in veterinary medicine and that were recently proposed as human anticancer agents, meets these requirements. The activity of salinomycin, monensin, and nigericin on Plasmodium falciparum asexual and sexual erythrocytic stages and on the development of the Plasmodium berghei and P. falciparum mosquito stages is reported here. Gametocytogenesis of the P. falciparum strain 3D7 was induced in vitro, and gametocytes at stage II and III or stage IV and V of development were treated for different lengths of time with the ionophores and their viability measured with the parasite lactate dehydrogenase (pLDH) assay. The monovalent ionophores efficiently killed both asexual parasites and gametocytes with a nanomolar 50% inhibitory concentration (IC50). Salinomycin showed a fast speed of kill compared to that of standard drugs, and the potency was higher on stage IV and V than on stage II and III gametocytes. The ionophores inhibited ookinete development and subsequent oocyst formation in the mosquito midgut, confirming their transmission-blocking activity. Potential toxicity due to hemolysis was excluded, since only infected and not normal erythrocytes were damaged by ionophores. Our data strongly support the downstream exploration of monovalent ionophores for repositioning as new antimalarial and transmission-blocking leads.

Topics: Antimalarials; Cell Line; Erythrocytes; Hemolysis; Humans; Inhibitory Concentration 50; Ionophores; Molecular Structure; Monensin; Nigericin; Plasmodium berghei; Plasmodium falciparum; Pyrans

Aiming at development of multitarget drugs for the anticancer treatment, new silybin (SIL) conjugates with salinomycin (SAL) and monensin (MON) were synthesized, in mild esterification conditions, and their antiproliferative activity was studied. The conjugates obtained exhibit anticancer activity against HepG2, LoVo and LoVo/DX cancer cell lines. Moreover, MON-SIL conjugate exhibits higher anticancer potential and better selectivity than the corresponding SAL-SIL conjugate.

Topics: Animals; Antineoplastic Agents; BALB 3T3 Cells; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; Mice; Monensin; Pyrans; Silybin; Silymarin; Structure-Activity Relationship

Staphylococcus epidermidis, a coagulase-negative Staphylococcus, is the most important pathogen responsible for chronic nosocomial infections. These bacteria produce extracellular slime and form biofilms on various biotic and abiotic surfaces. Bacterial biofilms are very resistant to standard antimicrobial therapy and difficult to eradicate, so it is important to search for new more effective anti-biofilm agents, for example in the group of natural substances. The aim of the study was to examine the activity of two ionophores-salinomycin and monensin against clinical S. epidermidis strains, using MIC/MBC method and biofilm formation inhibition assay. Bacterial strains were tested also for slime production using Congo Red Agar. Both tested ionophore antibiotics showed the highest activity against planktonic bacteria of clinical as well as standard S. epidermidis strains and effectively inhibited the formation of bacterial biofilm.

Topics: Anti-Bacterial Agents; Biofilms; Cross Infection; Humans; Ionophores; Microbial Sensitivity Tests; Monensin; Pyrans; Staphylococcal Infections; Staphylococcus epidermidis

Ionophore antibiotics (IPAs) are polyether compounds used in broiler feed to promote growth and control coccidiosis. Most of the ingested IPAs are excreted into broiler litter (BL), a mixture of excreta and bedding material. BL is considered a major source of IPAs released into the environment as BL is commonly used to fertilize agricultural fields. This study investigated IPA biodegradation in BL and soil microcosms, as a process affecting the fate of IPAs in the environment. The study focused on the most widely used IPAs, monensin (MON), salinomycin (SAL), and narasin (NAR). MON was stable in BL microcosms at 24-72% water content (water/wet litter, w/w) and 35-60 °C, whereas SAL and NAR degraded under certain conditions. Factor analysis was conducted to delineate the interaction of water and temperature on SAL and NAR degradation in the BL. A major transformation product of SAL and NAR was identified. Abiotic reaction(s) were primarily responsible for the degradation of MON and SAL in nonfertilized soil microcosms, whereas biodegradation contributed significantly in BL-fertilized soil microcosms. SAL biotransformation in soil microcosms yielded the same product as in the BL microcosms. A new primary biotransformation product of MON was identified in soil microcosms. A field study showed that MON and SAL were stable during BL stacking, whereas MON degraded after BL was applied to grassland. The biotransformation product of MON was also detected in the top soil layer where BL was applied.

Topics: Animals; Anti-Bacterial Agents; Biodegradation, Environmental; Chickens; Fertilizers; Ionophores; Manure; Monensin; Pyrans; Soil Microbiology; Soil Pollutants; Temperature; Veterinary Drugs; Water

Standard methods of determining the ionophore sensitivity of Eimeria rely on infecting chickens with an isolate or a mixture of Eimeria spp. oocysts in the presence of different anti-coccidial drugs. The purpose of this study was to develop a rapid in vitro method for assessing salinomycin and monensin sensitivity in Eimeria tenella. Cultures of MDBK cells were grown to 85% confluency, and then inoculated with excysted E. tenella laboratory strain (APU-1) sporozoites in the presence of different concentrations of salinomycin or monensin. At various timepoints, the monolayers were fixed for counting intraceullar sporozoites, or were subjected to DNA extraction, followed by molecular analysis using quantitative (qPCR) or semi-quantitative PCR (sqPCR). Preliminary experiments showed that 24h was the optimum time for harvesting the E. tenella-infected cell cultures. The average number of E. tenella sporozoites relative to untreated controls displayed a linear decrease between 0.3 and 33.0 μg/ml salinomycin and between 0.3 and 3.3 μg/ml monensin. A similar pattern was observed in the relative amount of E. tenella DNA as measured by sqPCR. A linear decrease in the relative amount of E. tenella DNA was observed over the entire range of salinomycin and monensin concentrations as measured by qPCR possibly reflecting the greater sensitivity of this assay. Comparison of sporozoite counting, sqPCR, and qPCR signals using a criterion of 50% inhibition in sporozoite numbers or level of PCR amplification product showed good agreement between the three assays. E. tenella field isolates (FS-1 and FS-2) displaying resistance to salinomycin and monensin were evaluated in the in vitro assay using qPCR and sqPCR. Compared to E. tenella APU-1, the E. tenella FS-1 and FS-2 isolates showed higher levels of E. tenella DNA at 24h by both qPCR and sqPCR. This in vitro assay represents a significant advance in developing rapid, cost-effective methods for assessing ionophore sensitivity in E. tenella.

Topics: Animals; Cell Culture Techniques; Chickens; Coccidiosis; Coccidiostats; Costs and Cost Analysis; Eimeria tenella; Ionophores; Monensin; Oocysts; Poultry Diseases; Pyrans; Real-Time Polymerase Chain Reaction; Sporozoites

Veterinary ionophore antibiotics (IPAs) are polyether compounds used extensively in the livestock industry to promote animal growth and prevent coccidia infection. However, the environmental fate and impact of IPAs are not fully understood. In this study, the inhibition and biotransformation potential of the most commonly used IPAs, monensin (MON) and salinomycin (SAL), were investigated under well-defined aerobic, nitrate-reducing, fermentative/sulfate-reducing, and fermentative/methanogenic conditions. Batch assays were conducted with mixed cultures developed from poultry litter (PL), PL-fertilized soil, and municipal anaerobic sludge. Significant transformation of MON and SAL was observed in aerobic, low-buffer capacity culture series as a result of abiotic acid-catalyzed IPAs hydrolysis induced by nitrification. Biotransformation of IPAs was the main transformation process in aerobic, high-buffer capacity culture series. MON persisted under fermentative/sulfate-reducing conditions, whereas SAL was transformed by fermentative bacteria. Both MON and SAL were stable under nitrate-reducing and methanogenic conditions. At IPAs concentrations up to 1 mg/L, MON inhibited only methanogenesis, whereas SAL did not impact any of the biological processes investigated in this study. Multiple, new primary IPA biotransformation products were observed on LC/MS, and their molecular structures were tentatively identified by analyzing LC/MS/MS fragmentation patterns. Overall, MON and SAL exhibited different inhibition and biotransformation patterns at each redox condition tested, which could greatly influence their fate and impact upon their release into the environment as a result of agricultural activities.

Topics: Aerobiosis; Anaerobiosis; Animals; Anti-Bacterial Agents; Bacteria; Biotransformation; Environment; Fermentation; Ionophores; Methane; Monensin; Nitrates; Oxidation-Reduction; Poultry; Pyrans; Sulfates; Time Factors; Veterinary Drugs; Waste Products

The veterinary ionophore antibiotics (IPAs) are extensively used as coccidiostats and growth promoters and are released to the environment via land application of animal waste. Due to their propensity to be transported with runoff, IPAs likely end up in surface waters where they are subject to photodegradation. This study is among the first to investigate the photodegradation of three commonly used IPAs, monensin (MON), salinomycin (SAL) and narasin (NAR), under UV and solar irradiation. Results showed that MON was persistent in a deionized (DI) water matrix when exposed to UV and sunlight, whereas SAL and NAR could undergo direct photolysis with a high quantum yield. Water components including nitrate and dissolved organic matter had a great impact on the photodegradation of IPAs. A pseudosteady state kinetic model was successfully applied to predict IPAs' photodegradation rates in real water matrices. Applying LC/MS/MS, multiple photolytic transformation products of IPAs were observed and their structures were proposed. The direct photolysis of SAL and NAR occurred via cleavage on the ketone moiety and self-sensitized photolysis. With the presence of nitrate, MON was primarily degraded by hydroxyl radicals, whereas SAL showed reactivity toward both hydroxyl and nitrogen-dioxide radicals. Additionally, toxicity tests showed that photodegradation of SAL eliminated its antibiotic properties against Bacillus subtilis.

Topics: Anti-Bacterial Agents; Ionophores; Kinetics; Monensin; Nitrates; Photolysis; Pyrans; Quantum Theory; Spectrum Analysis; Tandem Mass Spectrometry; Toxicity Tests; Ultraviolet Rays; Veterinary Drugs; Water; Water Pollutants, Chemical

Infection with human cytomegalovirus (HCMV) continues to be a threat for pregnant women and immunocompromised hosts. Although limited anti-HCMV therapies are available, development of new agents is desired. The Wnt signaling pathway plays a critical role in embryonic and cancer stem cell development and is targeted by gammaherpesviruses, Epstein-Barr virus (EBV), and Kaposi's sarcoma-associated herpesvirus (KSHV). HCMV infects stem cells, including neural progenitor cells, during embryogenesis. To investigate the role of Wnt in HCMV replication in vitro, we tested monensin, nigericin, and salinomycin, compounds that inhibit cancer stem cell growth by modulating the Wnt pathway. These compounds inhibited the replication of HCMV Towne and a clinical isolate. Inhibition occurred prior to DNA replication but persisted throughout the full replication cycle. There was a significant decrease in expression of IE2, UL44, and pp65 proteins. HCMV infection resulted in a significant and sustained decrease in expression of phosphorylated and total lipoprotein receptor-related protein 6 (pLRP6 and LRP6, respectively), Wnt 5a/b, and β-catenin and a modest decrease in Dvl2/3, while levels of the negative regulator axin 1 were increased. Nigericin decreased the expression of pLRP6, LRP6, axin 1, and Wnt 5a/b in noninfected and HCMV-infected cells. For all three compounds, a correlation was found between expression levels of Wnt 5a/b and axin 1 and HCMV inhibition. The decrease in Wnt 5a/b and axin 1 expression was more significant in HCMV-infected cells than noninfected cells. These data illustrate the complex effects of HCMV on the Wnt pathway and the fine balance between Wnt and HCMV, resulting in abrogation of HCMV replication. Additional studies are required to elucidate how HCMV targets Wnt for its benefit.

Topics: Animals; Antiviral Agents; Cell Line, Tumor; Cells, Cultured; Chlorocebus aethiops; Cytomegalovirus; Fibroblasts; Humans; Microbial Sensitivity Tests; Monensin; Nigericin; Pyrans; Vero Cells; Virus Replication; Wnt Signaling Pathway

Hydrolytic and photolytic degradation were investigated for the ionophore antibiotics lasalocid, monensin, salinomycin, and narasin. The hydrolysis study was carried out by dissolving the ionophores in solutions of pH 4, 7, and 9, followed by incubation at three temperatures of 6, 22, and 28 °C for maximum 34 days. Using LC-MS/MS for chemical analysis, lasalocid was not found to hydrolyse in any of the tested environments. Monensin, salinomycin, and narasin were all stable in neutral or alkaline solution but hydrolysed in the solution with a pH of 4. Half-lives at 25 °C were calculated to be 13, 0.6, and 0.7 days for monensin, salinomycin, and narasin, respectively. Absorbance spectra from each compound indicated that only lasalocid is degraded by photolysis (half-life below 1 h) due to an absorbance maximum around 303 nm, and monensin, salinomycin, and narasin are resistant to direct photolysis because they absorb light of environmentally irrelevant wavelengths.

Topics: Anti-Bacterial Agents; Half-Life; Hydrogen-Ion Concentration; Ionophores; Lasalocid; Models, Chemical; Monensin; Photolysis; Pyrans; Temperature; Water Pollutants, Chemical

Drug-drug interactions (DDIs) may adversely affect the prevention and cure of diseases. The effects of three polyether ionophore antibiotics, salinomycin (SAL), monensin (MON), and maduramycin (MAD) on the pharmacokinetics of florfenicol (FFC) were investigated in broilers. The chickens were fed rations with or without SAL (60 mg/kg feeds), MON (120 mg/kg feeds), or MAD (5 mg/kg feeds) for 14 consecutive days. FFC was given to the chickens either intravenously (i.v.) or orally (p.o.) at a single dose of 30 mg/kg body weight. Blood samples were taken from each chicken at 0-24 h postadministration of FFC. The plasma concentration of FFC was detected by high-performance liquid chromatography. The plasma concentration of FFC decreased with i.v. or p.o. co-administration of SAL, MON, or MAD in broilers, implying occurrence of DDIs during the co-administration of FFC with these ionophores. Our findings suggest that more attention should be given to the use of FFC to treat bacterial infections in chickens supplemented with polyether ionophore antibiotics.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Chickens; Chromatography, High Pressure Liquid; Coccidiostats; Drug Interactions; Drug Therapy, Combination; Injections, Intravenous; Ionophores; Lactones; Male; Monensin; Pyrans; Thiamphenicol

Ionophore antibiotics (IPAs) are polyether antimicrobials widely used in the livestock industry and may enter the environment via land application of animal waste and agricultural runoff. Information is scarce regarding potential transformation of IPAs under environmental conditions. This study is among the first to identify the propensity of IPAs to undergo acid-catalyzed transformation in mildly acidic aquatic systems and characterize the reactions in depth. The study focused on the most widely used monensin (MON) and salinomycin (SAL), and also included narasin (NAR) in the investigation. All three IPAs are susceptible to acid-catalyzed transformation. MON reacts much more slowly than SAL and NAR and exhibits a different kinetic behavior that is further evaluated by a reversible reaction kinetic model. Extensive product characterization identifies that the spiro-ketal group of IPAs is the reactive site for the acid-catalyzed hydrolytic transformation, yielding predominantly isomeric and other products. Toxicity evaluation of the transformation products shows that the products retain some antimicrobial properties. The occurrence of IPAs and isomeric transformation products is also observed in poultry litter and agricultural runoff samples. Considering the common presence of mildly acidic environments (pH 4-7) in soils and waters, the acid-catalyzed transformation identified in this study likely plays an important role in the environmental fate of IPAs.

Topics: Acetic Acid; Anti-Bacterial Agents; Bacillus subtilis; Hydrochloric Acid; Hydrogen-Ion Concentration; Ionophores; Kinetics; Models, Chemical; Monensin; Pyrans; Soil Pollutants

For the first time a direct and practical approach to the synthesis of eight amide derivatives of polyether antibiotic-salinomycin is described. The structure of allyl amide (3a) has been determined using X-ray diffraction. Salinomycin and its amide derivatives have been screened for their in vitro antimicrobial activity against the typical gram-positive cocci, gram-negative rods and yeast-like organisms, as well as against a series of clinical isolates of methicillin-resistant Staphylococcus aureus and methicillin-sensitive S. aureus. Amides of salinomycin have been found to show a wide range of activities, from inactive at 256 μg/mL to active with MIC of 2 μg/mL, comparable with salinomycin. As a result, phenyl amide (3b) was found to be the most active salinomycin derivative against gram-positive bacteria, MRSA and MSSA.

Topics: Amides; Anti-Bacterial Agents; Ether; Hydrogen Bonding; Models, Molecular; Molecular Structure; Pyrans; Staphylococcus aureus; Structure-Activity Relationship

Monensin is a polyether ionophore antibiotic that is widely used in the control of coccidia in animals. Despite its significance in veterinary medicine, little is known about its mode of action and potential mechanisms of resistance in coccidian parasites. Here we show that monensin causes accumulation of the coccidian Toxoplasma gondii at an apparent late-S-phase cell cycle checkpoint. In addition, experiments utilizing a monensin-resistant T. gondii mutant show that this effect of monensin is dependent on the function of a mitochondrial homologue of the MutS DNA damage repair enzyme (TgMSH-1). Furthermore, the same TgMSH-1-dependent cell cycle disruption is observed with the antiparasitic ionophore salinomycin and the DNA alkylating agent methyl nitrosourea. Our results suggest a novel mechanism for the mode of action of monensin and salinomycin on coccidial parasites, in which the drug activates an MSH-1-dependent cell cycle checkpoint by an unknown mechanism, ultimately leading to the death of the parasite. This model would indicate that cell cycle disruption is an important mediator of drug susceptibility and resistance to ionophoric antibiotics in coccidian parasites.

Topics: Animals; Anti-Bacterial Agents; Cell Cycle; DNA Repair; Ionophores; Monensin; MutS Homolog 2 Protein; Protozoan Proteins; Pyrans; Toxoplasma

The effects of ionophore antibiotics on the enzyme activity, protein and mRNA expression levels of cytochrome P450 (CYP) isoenzymes were investigated in liver from male Arbor Acres (AA) broiler chicks. Monensin, salinomycin and maduramycin at the dosage of 120, 60, and 5 mg/kg were administered in feed for 14 days. CYP1A and CYP3A activities were quantitated using cocktail probe drugs and a high performance liquid chromatographic (HPLC) assay at the 15th day; the protein expressions of CYP1A and CYP3A were detected by Western blot. CYP1A4, CYP1A5 and CYP3A37 mRNA levels were detected by real-time polymerase chain reaction (real-time PCR). Monensin, salinomycin and maduramycin had no effect on caffeine metabolism, protein expression and mRNA expression, but did induce dapsone metabolism, increasing CYP3A protein expression. However, there was no change in CYP3A37 mRNA expression as compared with the control group. It is suggested that ionophore antibiotics may have an induction effect on CYP3A expression and enzyme activity and that such effect might be related to the posttranscriptional regulation of its protein expression. Consideration of the enhanced metabolism of other drugs used simultaneously with ionophores is therefore recommended.

Topics: Animals; Blotting, Western; Caffeine; Chickens; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP3A; Dapsone; Dose-Response Relationship, Drug; Gene Expression; Ionophores; Lactones; Liver; Male; Microsomes, Liver; Monensin; Pyrans; Reverse Transcriptase Polymerase Chain Reaction; RNA Processing, Post-Transcriptional; RNA, Messenger

Polymyxin B (PMB) acts selectively on Gram-negative bacteria by electrostatic and hydrophobic interactions with anionic cell envelope components such as phospholipids and lipopolysaccharides. In this study, PMB was shown to exhibit marked fungicidal activity against yeasts and filamentous fungi in combination with ionophores such as salinomycin (SAM) and monensin (MON), which can selectively interact with monovalent cations. Ca(2+)-selective ionophores, A23187 and ionomycin, were absolutely ineffective in enhancing the fungicidal activity of PMB. SAM and MON increased the rate of cellular uptake of PMB possibly in favor of its intracellular action on the organelle. PMB could indeed directly disrupt the spherical membrane-enclosed architecture of the isolated vacuoles equally in the absence and presence of the ionophores. The loss of energy barrier for transmembrane transport of monovalent cations is considered to be a cause of enhanced incorporation of larger cationic compounds such as PMB across fungal plasma membrane.

Topics: Anti-Bacterial Agents; Antifungal Agents; Aspergillus niger; Bacteria; Candida albicans; Cell Membrane; Chromatography, High Pressure Liquid; Drug Synergism; Fungi; Ionophores; Lipid Peroxidation; Microbial Sensitivity Tests; Monensin; Phospholipids; Polymyxin B; Pyrans; Saccharomyces cerevisiae; Vacuoles

MutS homologues (MSHs) are critical components of the eukaryotic mismatch repair machinery. In addition to repairing mismatched DNA, mismatch repair enzymes are known in higher eukaryotes to directly signal cell cycle arrest and apoptosis in response to DNA-damaging agents. Accordingly, mammalian cells lacking certain MSHs are resistant to chemotherapeutic drugs. Interestingly, we have discovered that the disruption of TgMSH-1, an MSH in the pathogenic parasite, Toxoplasma gondii, confers drug resistance. Through a genetic selection for T. gondii mutants resistant to the antiparasitic drug monensin, we have isolated a strain that is resistant not only to monensin but also to salinomycin and the alkylating agent, methylnitrosourea. We have shown that this phenotype is due to the disruption of TgMSH-1 as the multidrug-resistance phenotype is complemented by a wild-type copy of TgMSH-1 and is recapitulated by a directed disruption of this gene in a wild-type strain. We have also shown that, unlike previously described MSHs involved in signalling, TgMSH-1 localizes to the parasite mitochondrion. These results provide the first example of a mitochondrial MSH that is involved in drug sensitivity and implicate the induction of mitochondrial stress as a mode of action of the widely used drug, monensin.

Topics: Amino Acid Sequence; Animals; Antiprotozoal Agents; Cloning, Molecular; DNA Repair; Drug Resistance; Genetic Complementation Test; Methylnitrosourea; Mitochondrial Proteins; Molecular Sequence Data; Monensin; Mutagenesis, Insertional; Mutation; MutS Homolog 2 Protein; Protozoan Proteins; Pyrans; RNA, Protozoan; Toxoplasma

Polyether antibiotics such as monensin and salinomycin have been primarily used as coccidiostat and growth promoter. Since residues of these antibiotic in food may pose a health risk for sensitive individuals, their use should be carefully monitored. An immunochemical method was developed for the determination of polyether antibiotic using monoclonal antibody (Mab) produced by immunized mice. Conjugates of monensin, salinomycin and laidlomycin were prepared with bovine serum albumin (BSA), keyhole limpet haemocyanine (KLH) and ovalbumin (OVA) by mixed anhydride method and then used as immunogene to produce Mab. Eight hybridoma cell lines were isolated that produced Mabs that competed with polyether antibiotic-protein conjugates in BALB/c-SP2/0 fusion system. Two hybridoma with higher sensitivity, designated as 4G11F and 1C8F1F, were cultured for mass production and then purified from ascites fluid. Antibiotic-protein conjugates were quantitavely analyzed by using the purified Mabs through a competitive enzyme-linked immunosorbent assay (ELISA).

Topics: Animals; Anti-Bacterial Agents; Antibodies, Monoclonal; Antibody Specificity; Cell Line; Enzyme-Linked Immunosorbent Assay; Ethers; Female; Hemocyanins; Hybridomas; Immunization; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Monensin; Ovalbumin; Pyrans; Serum Albumin, Bovine

A published confirmatory method for the quantitative determination of four ionophoric coccidiostats (lasalocid, monensin, salinomycin and narasin) in eggs and broiler meat has been further developed. It is proposed for replacement of liquid chromatography methods previously used in analysis of ionophoric coccidiostats. The samples were extracted with acetonitrile and purified on a silica solid phase extraction column. Purified samples were analysed by liquid chromatography-mass spectrometry and the method, was validated according to the Commission Decision 2002/657/EC. The validation parameters selectivity, linearity, specificity, precision, recovery, decision limit (CCalpha) and detection capability (CCbeta) were determined. The recoveries of coccidiostats analysed ranged from 64-99% in eggs and 62-100% in broiler meat. CCalpha varied from 0.8-1.4 microg/kg in eggs and from 1.5-2.5 microg/kg in broiler meat. CCbeta varied from 0.9 microg/kg to 2.0 microg/kg in eggs and from 1.7-3.2 microg/kg in broiler meat.

Topics: Animals; Chickens; Chromatography, Liquid; Coccidiostats; Eggs; Food Contamination; Lasalocid; Mass Spectrometry; Meat; Monensin; Pyrans; Reproducibility of Results

A sensitive and selective liquid chromatographic tandem mass spectrometric method (LC/MS/MS) for the simultaneous detection of the ionophoric coccidiostats narasin, monensin, lasalocid and salinomycin in whole eggs has been developed. A very simple sample preparation consisting of an extraction with an organic solvent was carried out. Sample extracts were injected into the LC/MS/MS system on a C18 column and an isocratic elution was performed. Nigericin was used as internal standard. The precursor ions produced by electrospray positive ionisation were selected for collisional dissociation with argon into product ions. Validation of the methods was performed based on Commission Decision 2002/657/EC.1 CC(alpha) was found to be 1 microg/kg for all four compounds. Monitoring of Belgian egg samples in 2004 revealed that residues of salinomycin, lasalocid and monensin could be found.

Topics: Animals; Chromatography, High Pressure Liquid; Coccidiostats; Eggs; Food Contamination; Ionophores; Lasalocid; Monensin; Pyrans; Spectrometry, Mass, Electrospray Ionization

Eimeria parasites were isolated from Nanhai Guangdong province (southern China) and studied in chickens in wire cages to evaluate their drug resistance against commonly used ionophores: monensin (100 mg/kg of feed), lasolacid (90 mg/kg), salinomycin (60 mg/kg), maduramicin (5 mg/kg) and semduramicin (25 mg/kg). Chinese Yellow Broiler Chickens were infected with 40,000 crude sporulated Eimeria oocysts at 15 days of age and prophylactic medication commenced a day prior to infection. Drug resistance was assessed for each ionophore drug by calculating the anticoccidial index (ACI) and percentage optimum anticoccidial activity (POAA) based on relative weight gain, rate of oocyst production and lesion values. Results revealed that Nanhai Eimeria oocysts comprising of E. tenella, E. maxima and E. acervulina, were resistant to monensin, sensitive to both salinomycin and lasolacid and partially sensitive to maduramicin and semduramicin. By selection for early development of oocysts during passage through chickens, the prepatent time of E. tenella, E. maxima and E. acervulina were reduced by 49, 36 and 22 h, respectively. The precocious lines are less pathogenic than the parent strains from which they were selected and conferred a satisfactory protection for chickens against coccidiosis. These ionophore-tolerant precocious lines could have wider applications in the development of anticoccidial vaccines for sustainable control of coccidiosis.

Topics: Animals; Chickens; Coccidiosis; Coccidiostats; Drug Resistance; Eimeria; Eimeria tenella; Ionophores; Lactones; Lasalocid; Monensin; Nigericin; Oocysts; Parasitic Sensitivity Tests; Poultry Diseases; Pyrans; Random Allocation; Treatment Outcome

The fragmentation pathways of two selected ionophore antibiotics, salinomycin and monensin A, were studied using electrospray (ES) orthogonal acceleration quadrupole time-of-flight mass spectrometry in positive-ion mode. The identity of fragment ions was determined by accurate-mass measurements. In ES mass spectra, ion signals of relatively high intensity were observed for [M+Na](+) and [M-H+2Na](+) for each antibiotic. Each of the ion species [M+Na](+) and [M-H+2Na](+) for salinomycin and [M-H+2Na](+) for monensin A were isolated in turn and subjected to fragmentation. In the fragmentation of [M+Na](+) and [M-H+2Na](+) from salinomycin, only Cbond;C single bond cleavage and dehydration were observed. Product ion mass spectra obtained from [M-H+2Na](+) of monensin A showed that ether ring opening, Cbond;C single bond cleavage and dehydration fragmentations had occurred. Fragment ions containing two sodium atoms were observed in the product ion mass spectrum of [M-H+2Na](+) from salinomycin, but not from monensin A. Both type A (containing the terminal carboxyl group) and type F (containing the terminal hydroxyl group) fragment ions were observed in the product ion mass spectra of sodium adduct ions of salinomycin and monensin A.

Topics: Anti-Bacterial Agents; Mass Spectrometry; Molecular Structure; Molecular Weight; Monensin; Pyrans

The chemotherapeutic efficacy of 6 in-feed compounds against Ichthyophthirius multifiliis Fouquet, 1876 was assessed using experimental infections of rainbow trout Oncorhynchus mykiss (Walbaum) fingerlings. Trial doses of 104 ppm amprolium hydrochloride or 65 ppm clopidol fed to fish for 10 d prior to infection significantly reduced the number of trophonts establishing in trout fingerlings by 62.0 and 35.2% respectively. In-feed treatments of infected trout with either 63 or 75 ppm amprolium hydrochloride, 92 ppm clopidol, or 38, 43 or 47 ppm salinomycin sodium for 10 d also significantly reduced the number of surviving trophonts by 77.6 and 32.2% for amprolium, 20.1% for clopidol and 80.2, 71.9 and 93.3% respectively for salinomycin sodium.

Topics: Administration, Oral; Amprolium; Animal Feed; Animals; Antiprotozoal Agents; Ciliophora; Ciliophora Infections; Clopidol; Decoquinate; Dose-Response Relationship, Drug; Fish Diseases; Monensin; Nicarbazin; Oncorhynchus mykiss; Pyrans; Random Allocation; Treatment Outcome

Little is known about the effects of residual veterinary drugs on the allergic reaction, except for the antigenicity of antibiotics and synthetic antimicrobials. Therefore, 59 kinds of veterinary drugs were investigated for their effects on the IgE receptor-mediated beta-hexosaminidase release from RBL-2H3 cells as an index of immediate allergic reaction. We found that the antibiotics chlorotetracycline, doxycycline, monensin, the synthetic antimicrobial pyrimethamine and the steroid hormone testosterone inhibited beta-hexosaminidase release. Most of the veterinary drugs showed no action, though the ionophores lasalocid, salinomycin and the steroid hormone hexestrol promoted beta-hexosaminidase release from injured cells. Based on the residual levels of these drugs and the frequencies of detection in actual food samples, it seems unlikely that these drugs have any immediate allergic effect in practice.

Topics: Animals; Anti-Bacterial Agents; beta-N-Acetylhexosaminidases; Chlortetracycline; Doxycycline; Drug Residues; Hexestrol; Hypersensitivity, Immediate; Lasalocid; Leukemia, Experimental; Monensin; Pyrans; Pyrimethamine; Rats; Receptors, IgE; Testosterone; Tumor Cells, Cultured; Veterinary Drugs

The construction and electrochemical response characteristics of four polyvinylchloride (PVC) membrane sensors for the determination of monensin (MN) and salinomycin (SL) were described. The membranes were prepared using 1 wt.% drug, 44 wt.% nitrophenyl octyl ether, 53 wt.% PVC and 2 wt.% lipophilic additive which is the anionic potassium tetra (4-chlorophenyl) borate in sensors 1 and 2 and the cationic nicklo-phenanthroline in sensors 3 and 4. Sensor 1 and sensor 2 show linear responses over concentration range of 10(-3)-10(-5) M drug with cationic slopes of 52.3 and 54.1 mV per concentration decade, respectively. On the other hand sensor 3 and sensor 4 show linear responses over concentration range 10(-4)-10(-5) M drug with anionic slopes of 28.1 and 29.7 mV per concentration decade, respectively. The 4 sensors were successfully applied to the determination of MN and SL in their pharmaceutical products (Premix) with average recoveries of 98.4-100.4+/-2.41-1.97% for sensors 1 and 2 and 97.6-98.8+/-3.16-3.07% for sensors 3 and 4. The obtained results were compared reasonably well with the data obtained using the USP method (2000). The proposed sensors were also applied for the direct determination of both drugs in animal feed preparations without prior treatment in low levels; 10-1000 microg per 5 g feed. The sensors were successfully used to follow up the drugs concentration in the presence of other growth promotors, other antibiotics and the coexisting fatty acids.

Topics: Animal Feed; Biosensing Techniques; Electrochemistry; Food Analysis; Growth Substances; Ionophores; Monensin; Polyvinyl Chloride; Pyrans; Reproducibility of Results

A rapid and very effective analytical procedure for the simultaneous determination of four polyether antibiotics (PEs) lasalocid, monensin, salinomycin and narasin in poultry feeds was tested. PEs were extracted from samples using methanol and without and clean-up derivatized with 2,4-dinitrophenylhydrazine (DNP) in an acidic medium at 55 degrees C. The derivatization mixture was analyzed directly on an ODS column (150 x 4.6 mm, 5 microns) with methanol--1.5% aqueous acetic acid (90:10, v/v) as eluent and UV detection was carried out at 305/392 nm. The recoveries of the PEs from spiked samples were 85-100% with RSDs of 4-10% in a concentration range of 50-150 mg/kg.

Topics: Animal Feed; Animals; Chromatography, Liquid; Coccidiostats; Indicators and Reagents; Lasalocid; Monensin; Phenylhydrazines; Poultry; Pyrans; Reference Standards; Reproducibility of Results; Spectrophotometry, Ultraviolet; Veterinary Drugs

The aim of this study was to evaluate the effect of different antibiotics used as growth promoters on the control of porcine intestinal adenomatosis when administered in weaning, growing and fattening pig diets, according to Annex I of the European Union directive (70/524/EEC and its subsequent amendments to date) for the use of feed additives. On a farm with a previous history of proliferative enteropathy outbreaks, 648 weaned piglets (23 days old) were divided into nine experimental groups according to bodyweight and sex ratio, each group comprising four pens with 18 pigs in each pen. One group served the trial as a negative (unmedicated) control: another (the positive control) received monensin via feed at 100 p.p.m. up to the end of the growing phase (107 days old) and 50 p.p.m. up to slaughter age (156 days old). The remaining seven groups were offered feed with the addition of the following antibiotics: virginia-mycin (50-20 p.p.m.), avilamycin (40-20 p.p.m.), spiramycin (50-20 p.p.m.), zinc bacitracin (50-10 p.p.m.), avoparcin (40-20 p.p.m.), tylosin (40-20 p.p.m.) and salinomycin (60-30 p.p.m.), respectively. The performance of the pigs in the positive control group was very satisfying and among the highest in the trial, verifying earlier field studies. As a general conclusion it seems that all tested growth promoters had a beneficial effect compared with the untreated control, indicated by the decrease of mortality rate, the elimination of diarrhoeal incidence and the enhancement of growth performance, although the proliferative enteropathy control achieved by each substance was not always satisfactory. More specifically, the antibiotic growth promoters tested can be scaled according to their total efficacy as follows: 1. Salinomycin, tylosin, spiramycin; 2. Virginiamycin, zinc bacitracin, avilamycin; and 3. Avoparcin. Finally, it is considered that part of the growth promotion efficacy of the tested substances is due to their potential capacity to control porcine intestinal adenomatosis; thus, in future growth performance trials, the disease background of the trial farms must be examined, especially for porcine enteropathy challenges.

Topics: Abattoirs; Animals; Anti-Bacterial Agents; Antibiotic Prophylaxis; Bacitracin; Bacterial Infections; Disease Outbreaks; Female; Food, Fortified; Glycopeptides; Greece; Growth Substances; Ileitis; Ileum; Intestinal Mucosa; Male; Monensin; Oligosaccharides; Pyrans; Spiramycin; Swine; Swine Diseases; Tylosin; Virginiamycin

Seven anticoccidial drugs commonly used in poultry (diclazuri), monensin, salinomycin, halofuginone, nicarbazin, robenidine, amprolium, and lasalocid) were tested for residual activity after withdrawal. In each test, the products were given at the recommended level to cages of 10 broiler chickens. Oral inoculation with coccidia was given after withdrawal of medication. Birds pretreated with 1 ppm of diclazuril and inoculated with Eimeria tenella after drug withdrawal had normal weight gain and very low lesion scores. Residual activity depleted gradually over several days, as shown by higher lesion scores when medication was withdrawn for up to 3 days before inoculation. Similar results were observed when young birds were inoculated with a mixture of E. tenella, E. maxima and E. acervulina, and also when birds were given diclazuril to market weight (6 weeks of age) and inoculated with a mixture of six species of Eiméria (The above species plus E. brunetti, E. mitis, and E. necatrix) after withdrawal of medication for 2 days. In contrast, there was no evidence of residual anticoccidial activity with nicarbazin, halofuginone, lasalocid, amprolium, salinomycin or monensin. Overall, the residual activity was unique to diclazuril.

Topics: Amprolium; Animal Feed; Animals; Chickens; Coccidiosis; Coccidiostats; Eimeria tenella; Feces; Female; Lasalocid; Male; Monensin; Nicarbazin; Nitriles; Piperidines; Poultry Diseases; Pyrans; Quinazolines; Quinazolinones; Random Allocation; Triazines

Coccidia were isolated from a commercial broiler farm with a history of suspected drug resistance. The sensitivity profiles of the Eimeria spp. isolates against the anticoccidial drugs nicarbazin (NIC), narasin (NAR), halofuginone (HAL), salinomycin (SAL), meticlorpindol plus methylbenzoquate (MET), and monensin (MON) at the recommended dose levels were followed in three battery trials (B1, B2, B3) corresponding to a field study over three periods of commercial broiler keeping (F1, F2, F3). Shuttle programs were performed in F1 (NIC/MON) and in F2 (MET/MON) while only SAL was used in F3. Eimeria acervulina and E. tenella were isolated from indicator birds in F1 while only E. acervulina could be found during F2 and F3. In trial B1 the isolate from F1 was identified as resistant against HAL and partly resistant against NIC and MON, the two drugs that were used in F1. Following the replacement of NIC in the starter feed by MET the respective isolate from F2 showed no resistance against ionophores (trial B2) while partial resistance against HAL was still present. Since SAL was the most efficient drug in B1 and B2 only this drug was applied in F3. Apart from a resistance against HAL no resistance against any of the other tested anticoccidials was found in the isolate from F3. SAL controlled coccidiosis efficiently in the field and best productivity was recorded in F3. This study shows that battery trials have a good predictive value in respect to the efficacy of anticoccidials under the conditions of commercial broiler production.

Topics: Animal Husbandry; Animals; Chickens; Clopidol; Coccidiosis; Coccidiostats; Drug Resistance; Eimeria; Feces; Food Industry; Ionophores; Monensin; Nicarbazin; Piperidines; Poultry Diseases; Predictive Value of Tests; Pyrans; Quinazolines; Quinazolinones; Quinolones

Monensin, salinomycin and narasin were detectable in six, two and one, respectively, out of 161 eggs surveyed in Northern Ireland in 1994. In all cases, the concentrations detected were less than 2.5 ng/g. Lasalocid was detectable in 107 eggs at concentrations ranging from 0.3 to 129 ng/g. Cross-contamination of unmedicated feeds with monensin during feed manufacture (up to eight batches of unmedicated feed contaminated with monensin) was similar to that previously observed for lasalocid (up to nine batches contaminated). Therefore differences in the incidence in eggs could not be explained by differential carry-over during feed manufacture. In a feeding trial it was shown that the relative ability of monensin, salinomycin and lasalocid to accumulate in eggs was in the ratio 0.12:3.3:63 ng/g egg per mg/kg feed, respectively. This indicated that the potential for monensin and salinomycin to cause residues in eggs was very low, by comparison with lasalocid. In 1995, a granular formulation of the lasalocid premix was introduced into the United Kingdom that decreased the carry-over of this drug from medicated to unmedicated feed. Six months after the introduction of this formulation, the incidence of lasalocid residues in eggs (21%) was lower than that found (66.5%) in an earlier survey (1994) carried out, and published, by this laboratory.

Topics: Animal Feed; Animals; Chickens; Coccidiostats; Drug Residues; Eggs; Food Contamination; Humans; Incidence; Ionophores; Lasalocid; Monensin; Northern Ireland; Pyrans

The effectiveness of Triancinolone as a protector against coccidiosis in broilers was tested in a random design experiment. Cobb x Cobb one-day old chicken were assigned to the treatments: T1: no medication-no inoculation; T2: no medication-inoculation; T3: Triancinolone-inoculation; T4: Sodic Monensin-inoculation; and T5: Sodic Salinomycin-inoculation. The inoculation was accomplished with 10,000 oocysts of Eimeria tenella and 40,000 of intestinal Eimerias. The results of the intestinal damage degree showed that T3 (60.6%) and T4 (63.6%) were better to control coccidias in relation to T5 (96.9%) and T2 (100%). The oocysts number in feces (number/g) showed the best effectiveness for T3 (4,300) comparing with T4 (126,900), T5 (98,100), and T2 (382,000). These results emphasize the effective action mechanism of Triancinolone to interfere with the biological cycle of coccidias. The feed conversion was better (P < 0.05) in the groups that received the drugs (T3, T4, and T5) comparing with T2. This fact showed the adverse effect that coccidiosis cause on the broiler performance behavior. Triancinolone showed the best action effectiveness on the control of coccidiosis.

Topics: Animals; Chickens; Coccidiosis; Coccidiostats; Eimeria; Evaluation Studies as Topic; Monensin; Pyrans; Triamcinolone; Weight Gain

Ten Eimeria field isolates from North Germany were studied in battery tests for sensitivity to selected anticoccidials. A high percentage of the Eimeria field isolates (9 out of 10) showed resistance to anticoccidials, mostly multiple resistance. Partial or complete resistance to maduramicin was found in 7 field isolates, to monensin in 6, to salinomycin in 5, to nicarbazin in 8, to halofuginone in 7, to robenidine and toltrazuril in 1, and to diclazuril in 2 field isolates. Multiple resistance had developed in 7 of the 10 isolates. Cross-resistance between maduramicin, monensin, and salinomycin occurred in 5 Eimeria isolates. One isolate showed cross-resistance between diclazuril and toltrazuril. From the resistant isolates 15 pure E. acerculina and 5 pure E. brunetti strains were obtained by single oocyst infections. Seven of the E. acerculina and 4 of the E. brunetti strains showed resistance or partial resistance that was also present in the original isolate. Ten of 11 resistant strains were multiply resistant.

Topics: Animals; Chickens; Coccidiosis; Coccidiostats; Drug Resistance; Drug Resistance, Multiple; Eimeria; Germany; Lactones; Male; Monensin; Nicarbazin; Nitriles; Piperidines; Poultry Diseases; Pyrans; Quinazolines; Quinazolinones; Robenidine; Triazines

A method is presented for the simultaneous determination of the three ionophores, monensin, salinomycin and narasin in muscle, liver and eggs from domestic fowl. Samples are homogenised in methanol and any ionophores present are extracted into toluene-hexane. The extracts are concentrated and injected into a bench-top electrospray LC-MS system. Chromatography is carried out using an end-capped reversed-phase column, with a mobile phase consisting a mixture of acetonitrile, methanol, tetrahydrofuran, trifluoroacetic acid and water. Using single-ion monitoring, the ionophores can be detected down to the 1 ng/g level.

Topics: Animals; Anti-Bacterial Agents; Chickens; Chromatography, High Pressure Liquid; Eggs; Liver; Mass Spectrometry; Monensin; Muscles; Pyrans; Reproducibility of Results; Sensitivity and Specificity; Tissue Distribution

This study examined the effects of feeding monensin, lasalocid or salinomycin (at 1x and 2x therapeutic levels for 20 d) on the duration of xylazine+ketamine sleep time and the hepatic cytochrome P-450 content in broiler chickens of different age groups (3- and 6-w-old). The 3-w-old birds fed 120 ppm salinomycin had a reduced xylazine+ketamine sleep time as compared to control (no drug). The 6-w birds had a sleep time similar to the controls. Associated with ionophore feeding was a trend toward P-450 induction when compared to controls. Increased P-450 content was statistically significant in the 3-w birds fed 90 ppm lasalocid and in the 6-w birds fed 200 ppm monensin. Ionophore administration above recommended levels gave conflicting results for duration of xylazine+ketamine sleep time and hepatic cytochrome P-450 levels. The isozymes of cytochrome P-450 responsible for xylazine and ketamine metabolism may be different from those induced by the ionophores. There was no significant age-related difference in ionophore effects on cytochrome P-450 content.

Topics: Analysis of Variance; Anesthetics, Dissociative; Animals; Chickens; Cytochrome P-450 Enzyme System; Ionophores; Ketamine; Lasalocid; Liver; Male; Monensin; Pyrans; Sleep; Xylazine

Fluorescein diacetate (FDA) and propidium iodide (PI) were used as indicators of membrane integrity after Eimeria tenella sporozoites were treated with polyether ionophores. Flow cytometry was used to quantitate the structural and functional effects based on red or green fluorescence and shape index of the sporozoites. Two field isolates (FS119 and FS139) were essentially resistant to polyether ionophores administered under practical conditions, whereas a laboratory strain was considered sensitive. The shape of sporozoites changed after treatment with ionophores, and this could be detected by flow cytometry. Green-fluorescing cells declined in number as the membranes were compromised by ionophore treatment. Red-fluorescing cells increased as the compromised membranes allowed entry of PI to bind with the nucleic acids. These effects were generally slower to develop in ionophore-tolerant field isolates compared with the sensitive laboratory strain. The effect of lasalocid on FDA and PI uptake, change in shape of the sporozoites, and lysis of sporozoites was more rapid than that of monensin or salinomycin. The 2 field isolates responded at different rates to salinomycin and monensin. Flow cytometry was a sensitive and accurate instrument for analysis of the effects of ionophores on sensitive and resistant lines of coccidia.

Topics: Animals; Cell Membrane Permeability; Coccidiostats; Eimeria tenella; Flow Cytometry; Fluoresceins; Fluorescent Dyes; Ionophores; Lasalocid; Monensin; Propidium; Pyrans

The effects of salinomycin (20 mg kg-1 feed), monensin (33 mg kg-1 feed) and a daily rotation of these ionophores, on average daily gain (ADG), average daily feed intake (ADFI) and feed conversion efficiency (FCE) were investigated in 60 steers (273 kg) over an 84-day feedlot period. Individual feed intakes and weight gains were recorded. The data were fitted to linear regressions with individual animals as replicates, from which ADGs, ADFIs and FCEs were calculated. Means of parameters of the control, salinomycin, monensin and rotation treatments were respectively ADG (kg): 1.56, 1.74, 1.58 and 1.66; FCE (kg DM/kg): 5.83, 5.43, 5.53 and 5.38; ADFI (kg): 9.10, 9.43, 8.83 and 8.90; final weight (kg): 402, 419, 407 and 413. Salinomycin showed the greatest improvement in gain, whereas monensin did not affect gain and tended to decrease feed intake. The rotation programme did not result in added benefits above those that could be obtained with a single ionophore (salinomycin), although feed efficiency tended to increase.

Topics: Animals; Body Weight; Cattle; Diet; Ionophores; Male; Monensin; Pyrans

The anticryptosporidial activities of three ionophorous antibiotics were assessed in dexamethasone-immunosuppressed rats infected with Cryptosporidium parvum. When administered prophylactically, lasalocid prevented infection in a dose-dependent manner, whereas monensin and salinomycin were ineffective. Therapeutically, lasalocid eliminated established overt infections of the intestine, although infection persisted in the common bile duct and intestinal infection recurred after lasalocid treatment was stopped. These findings suggest that lasalocid is a potentially useful anticryptosporidial agent but that long-term continuous administration may be necessary in the immunocompromised host.

Topics: Animals; Cryptosporidiosis; Cryptosporidium parvum; Female; Immunocompromised Host; Ionophores; Lasalocid; Monensin; Pyrans; Rats; Rats, Sprague-Dawley

The effect of salinomycin (2.5 mg/l) on the in vitro growth of Streptococcus bovis strain ATCC 9809, on its catabolism of glucose and on its anabolism of lactic acid was compared with that of monensin (5.0 mg/l). In control cultures containing no ionophore, glucose consumption and lactic acid production were completed concomitantly with maximal growth which was reached after 2 h of incubation at 37 degrees C. No further growth of S. bovis was observed within 2 h after the addition of one or the other ionophore to exponentially growing cultures. Glucose consumption and lactic acid production continued for 6 h after the addition of monensin and for 8 h after the addition of salinomycin. As observed in cultures without ionophore, glucose was totally consumed and lactic acid was stoichiometrically produced in cultures grown in the presence of one or the other ionophore. Thus, salinomycin and monensin inhibited bacterial growth but not fermentation of glucose by S. bovis.

Topics: Anti-Bacterial Agents; Fermentation; Glucose; Monensin; Pyrans; Streptococcus bovis

The efficacy of semduramicin (AVIAX), a novel polyether ionophore, was profiled in a series of 57 battery tests conducted in the United States and the United Kingdom. The studies employed mixed and monospecific infections of Eimeria acervulina, Eimeria mivati/Eimeria mitis, Eimeria brunetti, Eimeria maxima, Eimeria necatrix, and Eimeria tenella derived from North American and European field isolates. Ten-day-old broiler cockerels in pens of 8 to 10 birds were continuously medicated in feed beginning 24 h before challenge in tests of 6 to 8 days' duration. At the use level of 25 ppm, semduramicin effectively controlled mortality, lesions, and weight gain depression that occurred in unmedicated, infected controls for all species. In comparison with 60 ppm salinomycin, semduramicin significantly (P < .05) improved weight gain against E. brunetti and E. tenella, lesion control against E. brunetti and E. maxima, and the control of coccidiosis mortality against E. tenella. Salinomycin was superior (P < .05) to all treatments in maintenance of weight gain and control of lesions for E. acervulina. Maduramicin at 5 ppm was inferior (P < .05) to semduramicin in control of E. acervulina and E. maxima lesions, but was superior (P < .05) to all treatments in maintenance of weight gain and control of lesions in E. tenella infections. The data indicate that semduramicin at 25 ppm is well tolerated in broilers and possesses broad spectrum anticoccidial activity.

Topics: Animals; Anti-Bacterial Agents; Chickens; Coccidiosis; Eimeria; Lactones; Male; Monensin; Nigericin; Poultry Diseases; Pyrans; Species Specificity; Treatment Outcome; Weight Gain

Streptococcosis is a major disease of several fish species in Australia, Japan and South Africa. The minimum inhibitory concentration of some ionophores (lasalocid, monensin, narasin and salinomycin) was determined in vitro for an Enterococcus-like species pathogenic for rainbow trout (Oncorhynchus mykiss) in Australia. Forty isolates of the fish pathogen were tested, together with control strains of Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212 and Streptococcus bovis ATCC 9809. The minimum inhibitory concentrations (MIC) of erythromycin, the drug of choice for controlling streptococcosis, ranged between 0.1 and 0.8 microgram/ml whereas the MIC values for the ionophores ranged between 0.2 and 1.5 micrograms/ml. Of the ionophores tested, narasin was the most inhibitory (0.2-0.4 microgram/ml), while monensin was the least inhibitory (0.4-1.5 micrograms/ml). Salinomycin was marginally more inhibitory (0.4-0.8 microgram/ml) than lasalocid (0.8 microgram/ml).

Topics: Animals; Anti-Bacterial Agents; Enterococcus; Erythromycin; Fish Diseases; Gram-Positive Bacterial Infections; Ionophores; Lasalocid; Microbial Sensitivity Tests; Monensin; Oncorhynchus mykiss; Pyrans

The growth of mixed rumen fungi in vitro was suppressed by both ionophore antibiotics (salinomycin, monensin and portmicin) and polyoxins (polyoxin B and D: inhibitors of chitin synthesis). The fungistatic effect of the ionophores on a Piromonas spp. was more pronounced than on a Neocallimastix spp. The polyoxins, however, were more potent fungistatically against the Neocallimastix spp. than the Piromonas spp. Higher concentrations of the polyoxins were required to elicit the same effect as that observed with the ionophores. Salinomycin administration decreased fungal count in the rumen of sheep, but fungal count increased after the cessation of the feeding of the antibiotic. Polyoxin D also suppressed the growth of fungi in vivo, but the effect was short-lived. Nevertheless, both bacterial and protozoal counts tended to increase during and after the administration of polyoxin D. Total volatile fatty acid concentrations in the rumen tended to increase during the period of polyoxin D administration. This increasing tendency was maintained for 10 d after the cessation of antibiotic administration. Offering polyoxin D to sheep increased production of propionate (P < 0.05), while decreasing that of acetate. The results indicate that the rumen fungi are sensitive to chitin synthesis inhibitors as well as ionophores, and are essential members of microbes in the rumen ecosystem.

Topics: Acetates; Acetic Acid; Animals; Antifungal Agents; Bacteria; Butyrates; Butyric Acid; Chytridiomycota; Dose-Response Relationship, Drug; Eukaryota; Fatty Acids, Volatile; Ionophores; Monensin; Peptides; Propionates; Pyrans; Pyrimidine Nucleosides; Pyrroles; Rumen; Sheep

Broilers were grown to 42 days of age on diets supplemented with salinomycin (60 mg/kg), monensin (99 mg/kg), or halofuginone (3 mg/kg) and continued on unmedicated diets to 49 days of age. There were no significant (P greater than .05) differences among anticoccidials in final body weight, feed conversion, or mortality rates. Samples of birds were processed for dressing percentage and parts yield. Both males and females fed salinomycin had significantly higher breast meat yield as a percentage of postchill weight than those fed halofuginone but not those fed monensin; differences were not significant for breast meat yield of males or females fed monensin or halofuginone. Males fed halofuginone had significantly heavier leg quarters than those fed salinomycin but not those fed monensin. Females fed salinomycin had significantly higher water uptake during chill than those fed monensin or halofuginone. Results of the present study indicate that the anticoccidial used in growing broilers may influence some carcass yield parameters.

Topics: Animals; Body Weight; Chickens; Coccidiostats; Eating; Female; Male; Monensin; Muscle Development; Muscles; Piperidines; Pyrans; Quinazolines; Quinazolinones; Random Allocation

Topics: Animals; Chemical Phenomena; Chemistry; Chickens; Chromatography, Thin Layer; Ionophores; Lasalocid; Monensin; Pyrans

Because monensin and salinomycin are widely used to control coccidiosis, two experiments were conducted to compare the performance of broiler chicks when these compounds were added to the diet. Five levels of each coccidiostat were fed. Increasing the levels of coccidiostat resulted in a decrease in body weight and feed intake. Monensin gave a greater depression at the level suggested by the manufacturer for prevention of coccidiosis (121 ppm) than did salinomycin (66 ppm). The interaction of experiment x treatment was significant and was a result of the greater performance depression at the lower levels (manufacturers' recommended levels) of coccidiostat administered in the first experiment than in the second. This research points out the necessity of the accurate use of the coccidiostats.

Topics: Animals; Body Weight; Chickens; Coccidiostats; Female; Ionophores; Male; Monensin; Pyrans

The activities of five anticoccidials were compared against Eimeria species in/of chickens, in controlled in vivo and in vitro laboratory studies. Two more recent and potent market entries (maduramicin and halofuginone) were compared with three older polyether antibiotic anticoccidials (monensin, lasalocid and salinomycin). Halofuginone, lasalocid, maduramicin, monensin and salinomycin were evaluated at 3, 125, 5, 120 and 66 ppm, respectively, of active drug in the diets. At these levels, all five drugs demonstrated significant activity against Eimeria tenella, E. maxima, E. necatrix, E. brunetti and E. acervulina (in vivo). Monensin was least effective against E. tenella, and one of the lesser efficacious drugs against E. necatrix, maduramicin, was least effective against E. maxima. In studies of single Eimeria species infections, comparable weight gains were noted for the drugs. In the mixed Eimeria species infections, however, birds treated with maduramicin had significantly higher weight gains than did birds medicated with monensin. Unlike in vivo potencies, titration in vitro indicated that monensin was most potent (active at 10(-6) mcg ml-1), and maduramicin and lasalocid least potent (inactive at less than or equal to 10(-3) mcg ml-1).

Topics: Animals; Anti-Bacterial Agents; Body Weight; Chickens; Coccidiosis; Coccidiostats; Eimeria; Female; Ionophores; Lactones; Lasalocid; Male; Monensin; Piperidines; Poultry Diseases; Pyrans; Quinazolines; Quinazolinones

Topics: Animals; Chickens; Coccidiosis; Coccidiostats; Eimeria; Ionophores; Lasalocid; Monensin; Poultry Diseases; Pyrans

Topics: Animal Feed; Animals; Chickens; Coccidiostats; Female; Growth Disorders; Male; Monensin; Poultry Diseases; Pyrans

Chemoprophylaxis of Cryptosporidium baileyi infections was attempted by feeding 4 groups of chicks diets containing 3 mg of halofuginone/kg of feed, 60 mg of salinomycin/kg, 75 mg of lasalocid/kg, or 110 mg of monensin/kg. Rations were fed 5 days before oral or intratracheal inoculation with oocysts and were continued for 20 days. None of the drugs prevented C baileyi infections. Clinical signs of respiratory tract disease and gross lesions of airsacculitis were observed in intratracheally inoculated birds in all treatment groups and nonmedicated controls. Orally inoculated birds did not develop clinical signs of infection. Pathogenic bacteria were not isolated from the respiratory tract systems of any chicks. Halofuginone delayed the establishment of infections of the bursa of Fabricius and cloaca, but not of the trachea.

Topics: Animals; Chickens; Coccidiostats; Cryptosporidiosis; Lasalocid; Monensin; Piperidines; Poultry Diseases; Pyrans; Quinazolines; Quinazolinones

Alborixin, a polyether antibiotic with ionophore properties, was evaluated to determine the effect of the drug on weight gain of chickens and to define the anticoccidial spectrum of activity. The 50-ppm concentration in the diet was identified as the maximum level that did not significantly reduce weight gain beyond that of monensin (standard drug); consequently, the drug was evaluated for anticoccidial activity at this dilution. At the 50-ppm level, alborixin demonstrated broad-spectrum anticoccidial activity; however, the drug lacked Eimeria necatrix efficacy. Monensin and maduramycin were significantly more efficacious than alborixin as a treatment for several species of Eimeria. Higher concentrations of alborixin (greater than 50 ppm) appear essential to achieve broad-spectrum and comparable anticoccidial activity, however, these levels substantially depressed weight gains. Alborixin is similar to many other polyethers in that weight gains are adversely affected at drug levels essential for solid broad-spectrum anticoccidial activity.

Topics: Animals; Body Weight; Chickens; Coccidiostats; Eimeria; Monensin; Pyrans

A simultaneous determination of three polyether antibiotics, salinomycin, monensin and lasalocid, was established by silica gel and RP-18 high-performance thin-layer chromatography (HPTLC) using 18,19-dihydrosalinomycin and 18,19-dihydro-20-ketosalinomycin as internal standards. Fluorescent derivatives of the polyethers were prepared by reaction of their sodium salts with 1-bromoacetylpyrene and Kryptofix 222 in acetonitrile. A silica gel HPTLC plate with carbon tetrachloride-ethyl acetate-acetonitrile (50:5:10) as a solvent system and a RP-18 HPTLC plate with dichloromethane-ethyl acetate-acetone-acetonitrile (15:2:1:55) gave satisfactory separations of the five pyrenacyl esters of salinomycin, monensin, lasalocid, 18,19-dihydrosalinomycin and 18,19-dihydro-20-ketosalinomycin. Under these conditions the internal standard 18,19-dihydrosalinomycin was found to be suitable for the simultaneous determination of salinomycin and monensin, and 18,19-dihydro-20-ketosalinomycin for lasalocid. A linear relationship was obtained between the fluorescence intensity and the amount of each antibiotic in the range 2-14 ng. The detection limit of the three antibiotics was 100 pg.

Topics: Chromatography, Thin Layer; Densitometry; Lasalocid; Monensin; Pyrans; Solvents; Spectrometry, Fluorescence

Prophylactic levels of three ionophorous antibiotics, monensin, salinomycin, and lasalocid, were administered to groups of chickens and turkeys. All three ionophores markedly inhibited invasion of cecal tissues by sporozoites of ionophore-sensitive (IS) Eimeria tenella. Monensin and salinomycin also reduced invasion in turkeys by sporozoites of E. adenoeides, but lasalocid only minimally inhibited invasion. Invasion of ceca of monensin-medicated chickens was significantly greater by sporozoites of ionophore-resistant (IR) E. tenella than of the IS isolate. Concomitant experiments showed significant differences in [14C]monensin accumulation among IS and IR isolates of E. tenella. The decreased uptake of monensin by the IR isolates appeared to be accompanied by a decrease in responsiveness to the activity of monensin as well as to two other ionophores, salinomycin and narasin in cell culture. The amount of monensin, salinomycin or narasin required to inhibit development of E. tenella by 50% was 20 to 40 times higher for the IR isolates than for the IS ones. Collectively, the data suggest that differences in ionophore accumulation by IS and IR isolates of E. tenella might reflect differences in membrane chemistry and that these differences are responsible for the expressions of resistance that were observed in these studies. This expression of resistance appears to be common to all ionophores tested.

Topics: Animals; Chickens; Coccidiosis; Coccidiostats; Drug Resistance; Ionophores; Lasalocid; Monensin; Poultry Diseases; Pyrans; Turkeys

The efficacy of amprolium, monensin, and salinomycin in preventing coccidiosis in bobwhite quail was studied using a mixed inoculum of equal numbers of Eimeria dispersa and E. lettyae. A total dosage per quail of 10(6) sporulated oocysts was chosen because this dosage gave a good (77%) depression of weight gain from Day 18 to Day 24. Levels of .008% monensin or .0055% salinomycin were the most effective for prevention of coccidiosis as evaluated by body weight gains. These levels significantly reduced parasite numbers in the duodenum with monensin administration and in both the duodenum and ileum with salinomycin administration. Monensin reduced parasite numbers in the illeum significantly in one experiment and in a second. Amprolium was ineffective for prevention of coccidiosis, as evaluated by body weight gains. Amprolium was also ineffective in consistently reducing parasite numbers in the duodenum and ileum. Both monensin and salinomycin had a reasonable safety margin in quail. Levels of monensin of .016%, twice the proposed level, significantly reduced body weight at 14 days of age compared with unmedicated controls or quail given .008% monensin. By 28 days, however, this effect was no longer significant. Levels of salinomycin at the proposed level of .0055% significantly reduced body weight at 14 days of age compared with unmedicated controls. By 28 days, however, this effect was no longer significant in quail given .0055% or .00825% salinomycin, although in quail fed .011% salinomycin body weights remained significantly lower (16.5%) at that date. There were no detectable monensin residues in the liver of quail fed a ration containing .008% monensin for 8 wk.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amprolium; Animals; Bird Diseases; Coccidiosis; Coccidiostats; Colinus; Monensin; Pyrans; Quail

The effects of monensin and salinomycin (ionophorous antibiotics) on amylase release in the parotid glands were investigated in the superfused segments of sheep and rat. Monensin and salinomycin as well as acetylcholine and isoprenaline caused enhanced amylase release in a dose-dependent manner. Salinomycin was significantly more effective than monensin in both animals. The enhanced amylase release evoked by these ionophores and acetylcholine was significantly reduced in a calcium-free solution containing EGTA. From these results it is concluded that monensin and salinomycin transport calcium ions into the cytosol of parotid acinar cells from the extracellular fluid, resulting in amylase release.

Topics: Acetylcholine; Amylases; Animals; Anti-Bacterial Agents; Calcimycin; Calcium; Dose-Response Relationship, Drug; Female; Isoproterenol; Male; Monensin; Parotid Gland; Pyrans; Rats; Rats, Inbred Strains; Sheep

Rabbits spontaneously infected with coccidia of the genus Eimeria were treated with salinomycin, lasalocid and monensin. The drugs were applied in pellets in the doses of 50 ppm. The weight gain in rabbits treated with salinomycin and monensin was higher than in those treated with lasalocid and by 22.6% higher than in control animals. The weight gain in animals treated with lasalocid was almost the same as in the control group. The oocyst production was suppressed most significantly by salinomycin.

Topics: Animals; Coccidiosis; Coccidiostats; Lasalocid; Monensin; Pyrans; Rabbits

The fluorescent calcium indicator quin2 has been used for the first continuous measurement of the effects of pharmacological agents on intracellular calcium activity in isolated, perfused rabbit hearts. The average intracellular calcium activity was elevated after the infusion of norepinephrine, concurrent with increases in left ventricular pressure and heart rate. These changes were abolished by pretreatment of the heart with phentolamine and nadolol, alpha and beta adrenergic receptor antagonists, respectively. Pretreatment with phentolamine and nadolol did not eliminate the increases in left ventricular pressure and intracellular calcium activity caused by the infusion of the monovalent carboxylic ionophores monensin and salinomycin. It is concluded that the ionophores cause these effects by elevating intracellular sodium activity, which then raises the intracellular calcium activity of the myocardium through intracellular displacement and/or transcellular exchange. It is suggested that the use of fluorescent calcium indicators in intact organs could be useful in evaluating the role of calcium in a variety of pathological states.

Topics: Aminoquinolines; Animals; Calcium; Heart Rate; Ionophores; Mathematics; Monensin; Myocardial Contraction; Nadolol; Norepinephrine; Phentolamine; Pyrans; Rabbits; Sympathomimetics

Four isolates of Eimeria tenella obtained from the field were partially resistant to monensin. This resistance was not lost after 10 passages in unmedicated chickens, indicating that it was stable. One of the four isolates was examined and found to be resistant also to narasin, salinomycin and lasalocid.

Topics: Animals; Chickens; Coccidiosis; Coccidiostats; Drug Resistance, Microbial; Eimeria; Ionophores; Lasalocid; Monensin; Poultry Diseases; Pyrans

Five 7-day trials using 336, 24, 24, 40, and 40 Large White male turkeys when 7, 11, 15, 27, and 32 weeks of age, respectively, were conducted to determine the toxic effects of salinomycin. Salinomycin became more toxic as the age of the turkeys increased. When 7-week-old turkeys were fed diets containing 44 or 66 ppm salinomycin, only 1 of 84 died; when turkeys 27 or 32 weeks of age were fed those amounts, 13 of 20 died. Salinomycin at 22 ppm tended to depress rate of growth at young ages and to prevent or decrease growth and to increase mortality at older ages. Caution should be exercised to avoid salinomycin contamination of turkey diets.

Topics: Animals; Body Weight; Coccidiostats; Male; Monensin; Pyrans; Turkeys

Two, 7-week floor pen experiments were conducted consecutively with male broilers and then female broilers to determine the effects of feeding salinomycin (60 ppm), monensin (99 ppm), or lasalocid (125 ppm) at the following three levels of dietary protein: 1) that which meets National Research Council specifications (NRC, 1977), 2) that level deficient in sulfur amino acids (SAA), or 3) that deficient in protein. Group body weights, feed intake, and water consumption were noted at 28 and 49 days of age with feed efficiency and overall mortalities determined. Reducing SAA resulted in depressed (P less than .05) body weights at 7 weeks in both experiments, whereas deficient protein reduced (P less than .05) growth, feed efficiency, and water consumption. Generally, inclusion of coccidiostats in the diet did not significantly hinder growth or feed efficiency. Feeding of coccidiostats in combination with the low protein diet did not produce additional anorexigenic effects. Although a significant lasalocid SAA-sparing effect was not observed, diet X coccidiostat interactions (P less than .05) were apparent and attributable to an apparent "protein-sparing" effect upon body weight gain when salinomycin was fed in combination with the low protein diet. Lasalocid increased water consumption (P less than .05) relative to monensin in the female broilers.

Topics: Amino Acids, Sulfur; Animals; Body Weight; Chickens; Coccidiostats; Dietary Proteins; Drinking; Female; Food Additives; Lasalocid; Male; Monensin; Mortality; Pyrans; Sex Factors

Topics: Animal Feed; Chemical Phenomena; Chemistry; Chromatography, High Pressure Liquid; Furans; Monensin; Pyrans

Salinomycin, a new ionophore antibiotic, was tested and compared with lasalocid and monensin for preventing experimentally induced lactic acidosis. Five rumen-fistulated adult cattle were used in a 5 X 5 Latin square design, and the treatments were as follows: no treatment (control), 0.11 mg of salinomycin/kg of body weight (S1), 0.22 mg of salinomycin/kg (S2), 0.66 of lasalocid/kg, and 0.66 mg of monensin/kg. Acidosis was induced by intraruminal administration of a ground corn-corn starch mixture (50:50, 12.5 g/kg) once a day for up to 4 days. Antibiotics were administered along with grain-starch mixture. Rumen and blood samples were obtained before and at 6, 12, and 24 hours after each carbohydrate-antibiotic dosing to monitor acid-base status. Control and S1-treated cattle became ruminally acidotic within 54 hours, whereas cattle treated with S2, lasalocid, and monensin resisted acidosis for up to 78 hours after dosing. Cattle treated with S2, lasalocid, or monensin had higher rumen pH and lower L(+)- and D(-)-lactate concentrations than did control or S1-treated cattle. Rumen pH decrease to below 5.0 in S2-, lasalocid-, and monensin-treated cattle was not due to lactic acid, but to increased production of volatile fatty acids. Rumen propionate proportion increased initially in antibiotic-treated cattle, but after 48 hours, butyrate proportion increased significantly. Despite low rumen pH and high lactate concentration, lacticacidemia was not evident, and the systemic acid-base disturbance was mild in control cattle.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acidosis; Animal Feed; Animals; Cattle; Cattle Diseases; Food Additives; Hydrogen-Ion Concentration; Lactates; Lasalocid; Monensin; Pyrans; Rumen

The rate of feather growth was measured in Hubbard X Hubbard broilers given monensin, salinomycin, or lasalocid for 8 weeks in floor pens. Chicks were given a nutritionally adequate diet. Feathers on male chicks were shorter at 10 days of age but grew faster than those on female chicks. Male chicks had longer feathers than female chicks after 31 days of age. Back feather scores were similar in male and female chicks at 52 days of age. Dietary ionophores had no effect on the rate of feather growth or the back feather coverage under the condition of this study.

Topics: Animals; Body Weight; Chickens; Coccidiostats; Feathers; Female; Food Additives; Lasalocid; Male; Monensin; Pyrans; Sex Factors

Topics: Animal Feed; Anti-Bacterial Agents; Chromatography, Thin Layer; Furans; Lasalocid; Monensin; Pyrans

The effects of the monocarboxylic ionophore, salinomycin (K+-selective), on isometric twitches, high K+-induced contracture and transmembrane action potentials were compared with those of the monocarboxylic ionophore, monensin (Na+-selective), in isolated canine right ventricular muscle. In a concentration (5 X 10(-6) M) which did not produce changes in resting force, salinomycin increased peak active force (Po, + 170 +/- 36%, mean % change from control +/- S.D., P less than 0.01), and maximal rates of force development (dP/dt max, + 123 +/- 33%, P less than 0.01) and relaxation (-dP/dt max, + 180 +/- 40%, P less than 0.01) of the isometric twitch. A similar response pattern was found for 5 X 10(-6) M monensin (Po, + 90 +/- 24%, P less than 0.01; dP/dt max, + 137 +/- 19%, P less than 0.01; -dP/dt max, + 145 +/- 20%, P less than 0.01). In contrast to their effects on isometric twitches, salinomycin reduced peak K+ contracture force (Pc, -35 +/- 14%, P less than 0.01) whereas monensin increased it (Pc, + 30 +/- 12%, P less than 0.02). Ventricular muscle action potential duration was shortened similarly by the ionophores. beta-Adrenergic receptor blockade with nadolol diminished salinomycin's effects on the isometric twitch and K+ contracture, but not its effect to shorten the action potential. Monensin's actions were unaffected by nadolol. These results suggest that salinomycin's effects arise from both a direct modulation of K+ movement and the release of endogenous catecholamine. In contrast, monensin may act to alter intracellular Na+ which in turn leads to Na+-Ca2+ exchange and Ca2+-mediated modulation of K+ movement.

Topics: Action Potentials; Animals; Catecholamines; Dogs; Electrophysiology; Furans; Heart; In Vitro Techniques; Ionophores; Isometric Contraction; Monensin; Muscle Contraction; Myocardial Contraction; Potassium; Pyrans

In high concentrations, the ionophores salinomycin, monensin and X-537A cause cardiac arrhythmias in vivo. To determine if these arrhythmias result from a direct action of these ionophores on cardiac electrophysiology, we studied their effects on automaticity and transmembrane action potentials of isolated canine left ventricular Purkinje fibers. High concentrations of the ionophores suppressed automaticity and shortened action potential duration. These data suggest that high concentrations of the ionophores provoke cardiac arrhythmias in vivo by similar mechanisms despite their diverse cation transport selectivities.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Cations; Dogs; Heart Rate; Ionophores; Lasalocid; Monensin; Nadolol; Propanolamines; Purkinje Fibers; Pyrans

The effect of three polyether antibiotics (monensin, salinomycin, lasalocid) on developmental stages of Eimeria tenella (Coccidia, Sporozoa) was studied in vivo and in vitro by means of light and electron microscopy. It was found that these three drugs act against free merozoites, which are destroyed by bursting of the cell border (i.e. pellicle), endoplasmic reticulum and internal organelles even after very short exposure times (20 min) in media containing 1 ppm, 10 ppm or 100 ppm of these drugs. Sporozoites, however, survived these drug concentrations during an exposure time of 30 min (this would be sufficient to penetrate host cells and start development). Intracellular stages, which were situated in a parasitophorous vacuole within an intact host cell, were not attacked, apparently because these drugs are almost incapable of penetrating host cells. On the other hand, parasites (such as differentiated schizonts, gamonts) located within degenerating host cells showed slight disintegration, which did not necessarily led to their death. From these results it becomes clear why these polyether antibiotics have to be fed daily. Doses of 70 ppm salinomycin, 125 ppm monensin and 125 ppm lasalocid were found to bring about an equivalent protective effect against an infection with 40,000 Eimeria tenella oocysts.

Topics: Animals; Chickens; Coccidiosis; Coccidiostats; Eimeria; Furans; Lasalocid; Male; Microscopy, Electron; Monensin; Pyrans; Vacuoles

Sporozoites of Eimeria tenella were treated with different anticoccidial drugs in vitro and their subsequent viability was tested by inoculating them into chicken embryos. Monensin, salinomycin, lasalocid, and arprinocid, at concentrations between 0.01 and 1.0 micrograms/ml, greatly reduced sporozoite viability as judged by mortality, hemorrhage and specific lesions in the embryo chorioallantois. Monensin was also effective in reducing the viability of sporozoites of E. mivati and E. tenella as judged by oocyst production occurring in embryos; activity of monensin was greater against E. tenella than against E. mivati. Monensin (0.1 mg) inoculated into embryos inhibited development of E. tenella. Oocysts which were produced in the presence of the drug sporulated normally and sporozoites obtained from them were fully infective. By initiating treatment of chickens with monensin at different times in relation to infection, it was shown that the drug exerts its anticoccidial effect on the primary invasive stage and on the gametogonous stage of E. tenella and E. necatrix. The effect of gametogony was tested by initiating infections with second generation merozoites of E. tenella. Significant reduction in oocyst production occurred in three of four strains of E. tenella tested. Medication with monensin initiated before merozoite inoculation was effective in inhibiting oocyst production, but medication starting 5 hr after merozoite inoculation was not. This differed from the effects of arprinocid and sulfaquinoxaline which were expressed both before and 5 hr after merozoite inoculation. The results show that the ionophorous anticoccidial drugs exert their anticoccidial action primarily against the invasive stages of Eimeria.

Topics: Adenine; Animals; Chick Embryo; Coccidiosis; Coccidiostats; Eimeria; Furans; Ionophores; Lasalocid; Monensin; Pyrans; Temperature

Two ionophores, monensin and salinomycin, increased total cell Na+ and ouabain-sensitive 86Rb+ uptake in cultures of smooth muscle cells from rat aorta. Monensin was used to produce graded increases in cell Na+ in order to assess the Na+ dependence of the Na+/K+ pump in the intact cell. The relationship between internal Na+ and ouabain-sensitive 86Rb+ uptake was hyperbolic (K'Na = 3 mM). Monensin did not stimulate 86Rb+ uptake in the absence of external Na+. Loading the cells with Na+ by exposing cultures to a K+-free medium for 3 hr maximally increased cell Na+ and ouabain-sensitive 86Rb+ uptake to the same extent as monensin. Total cell Na+ and pump activity in monensin-treated cells returned to the initial values after removing the ionophore. Monensin was then able to increase total cell Na+ and ouabain-sensitive 86Rb+ uptake to the same extent as the initial treatment with the ionophore.

Topics: Animals; Aorta; Biological Transport, Active; Cells, Cultured; Furans; Ionophores; Methylglucosides; Monensin; Muscle, Smooth, Vascular; Potassium; Pyrans; Rats; Rubidium; Sodium

Free Eimeria tenella sporozoites were exposed to the anticoccidial ionophores monensin, lasalocid, narasin, or salinomycin for 4 hr at 40 C, whereupon the drugs were removed by dilution centrifugation and the parasites inoculated into cultures of chick kidney cells. Cultures were fixed and stained at 4 and 96 hr postinoculation to determine the effect of ionophore uptake by the extracellular sporozoites on invasion and development. Pretreatment with each of these antibiotics significantly reduced the number of intracellular sporozoites and dramatically inhibited asexual development. These effects were dose-dependent. Exposure of free (extracellular) sporozoites to monensin at 40 C caused a significant decline in the number of surviving organisms over time as compared to nontreated sporozoites. This response also appeared to be dose-dependent. Scanning and transmission electron microscopy revealed that the surface of the treated sporozoites was very irregular and the organisms often exhibited a gross swelling. These results indicated that free Eimeria tenella sporozoites may incorporate a potentially lethal concentration of the polyether ionophorous antibiotics and that a coccidiocidal activity may be expressed whether or not penetration of host's cells occurs.

Topics: Animals; Cells, Cultured; Chickens; Dose-Response Relationship, Drug; Eimeria; Furans; Ionophores; Kidney; Lasalocid; Monensin; Pyrans

Topics: Animals; Anti-Bacterial Agents; Chickens; Coccidiosis; Coccidiostats; Drug Combinations; Eimeria; Ionophores; Lasalocid; Male; Monensin; Poultry Diseases; Pyrans

Three polyether, ionophorous anticoccidial drugs were fed to broiler chickens in floor pens for 5 or 6 weeks, then withdrawn for 2 weeks or 1 week, respectively. With monensin and salinomycin there was evidence of increased feed consumption and compensatory growth during the first week, but not the second week, after drug withdrawal. There was no evidence of compensatory growth in birds fed lasalocid. Final weights were best in birds fed lasalocid and salinomycin in comparison with unmedicated controls and birds fed monensin. There was evidence of increased feed consumption and compensatory growth in some treatments in which birds weighed more than controls prior to drug withdrawal.

Topics: Animals; Antibodies; Body Weight; Chickens; Eating; Furans; Ionophores; Lasalocid; Monensin; Pyrans

Topics: Animals; Anti-Bacterial Agents; Coccidiosis; Eimeria; Female; Lasalocid; Male; Monensin; Pyrans; Rabbits; Species Specificity

The anticoccidial salinomycin has a cidal effect against chicken coccidia. Restricted and unrestricted medication studies and histopathological examinations of chicks infected with Eimeria acervulina, E. maxima, or E. tenella showed that parasites were destroyed within host cells during asexual development. Most sporozoites failed to become trophozoites and were destroyed 30--72 hr after ingestion of oocysts. The drug also affected schizonts during initial nuclear replication by either destroying or significantly delaying their maturation. Parasites affected by the drug were distorted grossly. Drug action against gametogony was not observed histologically, but when medication was restricted to this period of the life cycle, subsequent oocyst shedding of all 3 species was reduced by 20--70% compared to unmedicated controls. When drug was provided during the entire parasite life cycle, activity against asexual stages was so complete that only a limited number of parasites survived to form gamonts, and oocyst shedding was reduced by 80--90% relative to controls. As with other ionophores, salinomycin had no effect upon rate of oocyst sporulation.

Topics: Animals; Anti-Bacterial Agents; Chemical Phenomena; Chemistry; Chickens; Coccidiosis; Coccidiostats; Eimeria; Female; Male; Monensin; Pyrans; Reproduction, Asexual; Time Factors

Three experiments were designed to test the efficacy of salinomycin and stenorol against infection by various Eimeria species on cage reared broiler type chicks. Efficacy was based on a coccidial index. Sixty parts per million salinomycin alone or in combination with 50 ppm 3 nitro significantly improved the index over basal treatments or when 3 nitro was used alone. The differences in index values recorded for coban and salinomycin were not significant. Stenorol significantly improved the index and appeared to be a most effective anticoccidial product. Broiler chickens reared in floor pens to 8 weeks showed a significant reduction in weight gain when the diet contained salinomycin +3 nitro or coban. Stenorol at 3, 6, or 9 ppm reduced body weight, with linear regression for this effect being highly significant (P less than .01). No coccidiosis was observed.

Topics: Animals; Chickens; Coccidiosis; Coccidiostats; Ionophores; Male; Monensin; Piperidines; Poultry Diseases; Pyrans; Quinazolines; Quinazolinones; Roxarsone

Topics: Animals; Chickens; Coccidiosis; Coccidiostats; Furans; Ionophores; Lasalocid; Male; Monensin; Poultry Diseases; Pyrans

Topics: Animals; Anti-Bacterial Agents; Chickens; Coccidiosis; Coccidiostats; Furans; Lasalocid; Monensin; Poultry Diseases; Pyrans

Salinomycin (Coxistac), a new broad spectrum anticoccidial, was tested in broilers reared in floor pens for safety at 50, 60, 80, 100, and 160 ppm fed continuously from 1 to 56 days of age. Four trials were conducted. Comparisons were made to unmedicated controls and in three trials to monensin to monensin at 80, 100, and 121 ppm. The weight gains at 50 and 60 ppm of salinomycin and 80 and 100 ppm of monensin were statistically comparable and equivalent to or better than controls. The weight gain at 80 ppm of salinomycin was slightly below controls but comparable to 121 ppm monensin. Levels of 100 and 160 ppm of salinomycin depressed weight gain. Feed conversion for all treatments except 160 ppm salinomycin were comparable.

Topics: Animals; Anti-Bacterial Agents; Chickens; Coccidiostats; Female; Housing, Animal; Male; Monensin; Pyrans

Infections with single species of Eimeria acervulina, E. mivati, E. maxima, E. tenella, E. necatrix, and E. brunetti, and the six species mixed, were utilized in three separate battery experiments to evaluate the anticoccidial efficacy of various levels of salinomycin (AHR-3096), a fermentation product of a strain of Streptomyces albus. At the 60 to 100 p.p.m. treatment levels, this compound showed significant anticoccidial activity for all parameters studied (mortality, weight gain, feed conversion, dropping scores, and lesion scores). The mortality due to coccidiosis was reduced to 0.1% in the medicated infected birds. Some activity, as measured by weight gain, was seen in the lower levels of salinomycin medication (12.5 to 50 p.p.m.), but other parameters, including mortality and lesion scores, indicated less activity than that seen with the higher treatment levels. At 100 p.p.m., there was no apparent effect on the compound on bird performance in uninfected control birds. Salinomycin at the 100 p.p.m. treatment level was statistically as effective as 121 p.p.m. monensin (reference anticoccidial) in controlling coccidiosis.

Topics: Animal Feed; Animals; Anti-Bacterial Agents; Body Weight; Chickens; Coccidiosis; Coccidiostats; Intestines; Monensin; Poultry Diseases; Pyrans