piperidines and salinomycin

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

Salinomycin, an ionophore antibiotic, is known to be an effective agent in reducing the viability of Glioblastoma (GBM) cells. The combination of salinomycin with other chemotherapeutic drugs would help to overcome the drug resistance of GBM cells.. This study aims to test the combinatorial effect of salinomycin and AZD3463 in T98G GBM cells.. The cytotoxic effects of drugs on T98G GBM cells were determined by using WST-8 assay. Flow cytometry was used to identify apoptosis and cell cycle profiles after treatments. Real-time PCR was used to portray mRNA expression profiles of genes in the Wnt-signaling pathway after treatments.. IC50 concentrations of AZD3463 and salinomycin were 529nM and 7.3μM for 48h, respectively. The combination concentrations of AZD3463 and salinomycin were 3.3μM and 333nM, respectively. The combination treatment showed a synergistic effect on reducing the viability of GBM cells. AZD3463, salinomycin, and their combination induced apoptosis in 1.2, 1.4, and 3.2 folds, respectively. AZD3463 and the combination treatment induced the cell cycle arrest at the G1 phase. Salinomycin and AZD3463 treatments, either alone or in combination, resulted in the downregulation or upregulation of mRNA expression levels of genes in the Wntsignaling pathway.. Salinomycin, AZD3463, and their combination may inhibit proliferation and induce apoptosis in GBM cells due to a decrease in expression levels of genes acting in both the canonical and non-canonical Wnt signaling pathways. The Wnt signaling pathway may be involved in salinomycin-AZD3463 drug interaction.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Therapy, Combination; Glioblastoma; Humans; Indoles; Molecular Structure; Piperidines; Pyrans; Pyrimidines; Structure-Activity Relationship; Tumor Cells, Cultured

No disease-modifying treatment exists for the fatal neurodegenerative polyglutamine disease known both as Machado-Joseph disease and spinocerebellar ataxia type 3. As a potential route to therapy, we identified small molecules that reduce levels of the mutant disease protein, ATXN3. Screens of a small molecule collection, including 1250 Food and Drug Administration-approved drugs, in a novel cell-based assay, followed by secondary screens in brain slice cultures from transgenic mice expressing the human disease gene, identified the atypical antipsychotic aripiprazole as one of the hits. Aripiprazole increased longevity in a Drosophila model of Machado-Joseph disease and effectively reduced aggregated ATXN3 species in flies and in brains of transgenic mice treated for 10 days. The aripiprazole-mediated decrease in ATXN3 abundance may reflect a complex response culminating in the modulation of specific components of cellular protein homeostasis. Aripiprazole represents a potentially promising therapeutic drug for Machado-Joseph disease and possibly other neurological proteinopathies.

Topics: Animals; Animals, Genetically Modified; Antipsychotic Agents; Aripiprazole; Ataxin-3; Brain; Disease Models, Animal; Drosophila; Drug Evaluation, Preclinical; Gene Expression Regulation; HEK293 Cells; Humans; Machado-Joseph Disease; Mice; Mutant Proteins; Nerve Tissue Proteins; Organ Culture Techniques; Peptides; Piperidines; Pyrans; Pyrazoles

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

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

Live performance and carcass quality of female broilers were evaluated under four coccidiostat programs (CP) and two feed treatments. The CP consisted of halofuginone (H) and salinomycin (S), fed either continuously (HH and SS) or in rotational programs (HS and SH), during the starter (1 to 21 d) and grower (22 to 35 d) periods, respectively. All groups received an unmedicated withdrawal feed from 36 to 42 d. Feed treatments consisted of a control and a fortified diet high in proline and supplemented with additional ascorbic acid and zinc (50 birds per pen; 4 pens per feed; 8 pens per CP). In addition to live performance and skin puncture strength, carcass quality attributes following processing (at 43 d of age) were assessed. No CP by feed interactions were detected for any of the variables measured. The CP treatments did not differ for live performance. Birds on fortified feed were heavier at 21 d (P < .001) and had an improved feed conversion at 42 d (P < .05). Skin puncture strength was significantly reduced for the birds fed H, either in continuous (HH) or rotational programs (HS and SH). Skin sores-scratches and tears were lowest for the SS and SH groups. The HH treatment resulted in fewer grade A carcasses (P < .001). Halofuginone, when fed continuously or in the starter feed, affected carcass quality of broilers. Higher dietary proline or supplementation with ascorbic acid and zinc did not appear to alleviate the effects of halofuginone on skin quality.

Topics: Animals; Ascorbic Acid; Body Weight; Chickens; Coccidiostats; Female; Food, Fortified; Piperidines; Proline; Pyrans; Quinazolines; Quinazolinones; Skin; Skin Physiological Phenomena; Tensile Strength; Zinc

Live performance and skin characteristics of male and female broilers were evaluated under four coccidiostat feed additive programs. Treatments consisted of halofuginone (H) and salinomycin (S), fed either continuously (HH and SS) or in rotational programs (HS and SH) during the starter (1 to 21 d) and grower (22 to 35 d) periods, respectively. An unmedicated withdrawal feed was provided from 36 to 42 d of age. Body weights, feed efficiency, and mortality (by pen) were determined, in addition to skin puncture strength measurements taken at Days 21, 35, and 42 on five birds per pen. At 43 d of age, all birds were processed and individually graded for skin defects. There were no treatment by sex interactions for any variable measured. Male body weights, feed efficiency, and total mortality exceeded those of females (P < .05). Skin puncture strength was reduced at 21 d in the HH and HS groups, at 35 d in the HH and SH groups, and at 42 d in the HH, HS, and SH groups. Thigh sores and scratches were higher for the HH group (P < .05), and thigh skin tears were higher for the HH and HS groups (P < .01). Males had more swollen hock joints and breast blisters than females (P < .001). Females had more thigh skin tears (P < .01) and broken wings (P < .001) than males. Results of the present study demonstrated that halofuginone affected skin strength of broilers, especially when used continuously or only in the starter feed (1 to 21 d).

Topics: Animals; Body Weight; Chickens; Coccidiostats; Female; Food, Fortified; Male; Piperidines; Pyrans; Quinazolines; Quinazolinones; Sex Factors; Skin; Skin Physiological Phenomena; Tensile Strength

Continuous feeding of the anticoccidial halofuginone to broilers is associated with reduced skin tensile strength and increased skin tearing during processing. The possible mitigating effect of shuttle administration of halofuginone and salinomycin to female broilers was evaluated. Halofuginone or salinomycin were included in the starter and grower diets in all four possible combinations, with anticoccidial omitted from the finisher diets. Starter, grower, and finisher diets were fed to broilers through 3, 6, and 7 wk of age, respectively. Skin strength of pullets fed a diet based on milo and corn (NW) vs a diet based on corn was also compared in a factorial arrangement. Two further treatments were also included: 1) halofuginone-only NW diet supplemented with 2,500 ppm ascorbic acid from 0 to 7 wk; and 2) NW diet reared on wire floor without anticoccidial treatment. Skin tensile strength was determined at 3, 6, and 7 wk of age. Dietary composition had no effect upon skin strength or BW of broilers. Addition of ascorbic acid to the diet containing halofuginone anticoccidial did not improve skin strength. Continuous feeding of halofuginone reduced skin strength whereas withholding anticoccidial and continuous feeding of salinomycin resulted in high skin strength. When halofuginone was used in shuttle feeding programs with salinomycin, there were no differences in skin strength at 7 wk of age compared to birds that were continuously treated with salinomycin. These results suggest halofuginone may be used in a shuttle program either during the starter or grower phase without adverse affect on skin tensile strength at slaughter.

Topics: Animal Feed; Animals; Chickens; Coccidiostats; Diet; Drug Administration Schedule; Female; Piperidines; Pyrans; Quinazolines; Quinazolinones; Skin; Skin Physiological Phenomena; Tensile Strength

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

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

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

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