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Gracia Merino - One of the best experts on this subject based on the ideXlab platform.
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short communication the gain of function y581s polymorphism of the abcg2 transporter increases secretion into milk of Danofloxacin at the therapeutic dose for mastitis treatment
Journal of Dairy Science, 2015Co-Authors: Jon A Otero, Borja Barrera, J G Prieto, A I Alvarez, A De La Fuente, Margarita M Marques, Gracia MerinoAbstract:Abstract The ATP-binding cassette transporter ABCG2 restricts the exposure of certain drugs and natural compounds in different tissues and organs. Its expression in the mammary gland is induced during lactation and is responsible for the active secretion of many compounds into milk, including antimicrobial agents. This particular function of ABCG2 may affect drug efficacy against mastitis and the potential presence of drug residues in the milk. Previous in vitro and in vivo studies showed increased transport of several compounds, including fluoroquinolones, by the bovine ABCG2 Y581S polymorphism. Our main purpose was to study the potential effect of this bovine ABCG2 polymorphism on the secretion into milk of the antimicrobial Danofloxacin administered at the therapeutic dose of 6mg/kg used for mastitis treatment. In addition, the effect of this polymorphism on the relative mRNA and protein levels of ABCG2 by quantitative real-time PCR and Western blot were studied. Danofloxacin 18% (6mg/kg) was administered to 6 Y/Y homozygous and 5 Y/S heterozygous cows. Danofloxacin levels in milk and milk-to-plasma concentration ratios were almost 1.5- and 2-fold higher, respectively, in Y/S cows compared with the Y/Y cows, showing a higher capacity of this variant to transport Danofloxacin into milk. Furthermore, the higher activity of this polymorphism is not linked to higher ABCG2 mRNA or protein levels. These results demonstrate the relevant effect of the Y581S polymorphism of the bovine ABCG2 transporter in the secretion into milk of Danofloxacin after administration of 6mg/kg, with potentially important consequences for mastitis treatment and for milk residue handling.
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effects of triclabendazole on secretion of Danofloxacin and moxidectin into the milk of sheep role of triclabendazole metabolites as inhibitors of the ruminant abcg2 transporter
Veterinary Journal, 2013Co-Authors: Borja Barrera, Rebeca Real, L Gonzalezlobato, Jon A Otero, J G Prieto, A I Alvarez, Gracia MerinoAbstract:Abstract ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP) mediates drug–drug interactions that affect the secretion of drugs into milk. The aims of this study were: (1) to determine whether the major plasma metabolites of the flukicide triclabendazole (TCBZ), triclabendazole sulfoxide (TCBZSO) and triclabendazole sulfone (TCBZSO 2 ), inhibit ovine and bovine ABCG2 and its Y581S variant in vitro, and (2) to examine whether coadministration of TCBZ with the ABCG2 substrates Danofloxacin (a fluoroquinolone) and moxidectin (a milbemycin) affects the secretion of these drugs into the milk of sheep. TCBZSO and TCBZSO 2 inhibited ruminant ABCG2 in vitro by reversing the reduced mitoxantrone accumulation and reducing basal to apical transport of nitrofurantoin in cells transduced with bovine variants (S581 and Y581) and the ovine variant of ABCG2. Coadministration of TCBZ with moxidectin or Danofloxacin to sheep resulted in significantly reduced levels of moxidectin, but not Danofloxacin, in the milk of TCBZ-treated sheep compared to sheep administered moxidectin or Danofloxacin alone. The milk area under concentration time curve (AUC 0–48 h) was 2.99 ± 1.41 μg h/mL in the group treated with TCBZ and moxidectin, and 7.75 ± 3.58 μg h/mL in the group treated with moxidectin alone. The AUC (0–48 h) milk/plasma ratio was 37% lower in the group treated with TCBZ and moxidectin (7.34 ± 1.51) than in the group treated with moxidectin alone (11.68 ± 3.61). TCBZ metabolites appear to inhibit ruminant ABCG2 and affect the secretion of ABCG2 substrates into milk of sheep.
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inhibition of abcg2 bcrp transporter by soy isoflavones genistein and daidzein effect on plasma and milk levels of Danofloxacin in sheep
Veterinary Journal, 2013Co-Authors: Miriam Perez, Borja Barrera, Gracia Merino, Jon A Otero, J G Prieto, A I AlvarezAbstract:Abstract Danofloxacin is a synthetic fluoroquinolone antibacterial agent and a substrate for ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP). This protein actively extrudes drugs from cells in the intestine, liver, kidney, and other organs, such as the mammary gland. The purpose of this study was to determine whether genistein and daidzein, isoflavones present in soy and known inhibitors of ABCG2, could diminish Danofloxacin secretion into milk. The results obtained from BCRP-transduced MDCK-II cells (Mardin-Darby canine kidney) showed that both isoflavones efficiently inhibited the in vitro transport of the drug. In addition, Danofloxacin transport into milk was studied in Assaf sheep. The experimental design with ewes ( n = 18) included ewes fed with standard forage, soy-enriched forage for 15 days prior to the experiment or standard forage paired with orally administered exogenous genistein and daidzein. The Danofloxacin levels in the milk of ewes in the soy-enriched diet group were decreased. The area under concentration–time curve AUC (0–24 h) was 9.3 ± 4.6 vs. 16.58 ± 4.44 μg h/mL in the standard forage or control group. The plasma levels of Danofloxacin were unmodified. The AUC (0–24 h) milk/plasma ratio decreased by over 50% in the soy-enriched diet group, compared to the control group (4.90 ± 2.65 vs. 9.58 ± 2.17). Exogenous administration of isoflavones did not modify Danofloxacin secretion into milk. This study showed that milk excretion of a specific substrate of BCRP, such as Danofloxacin, can be diminished by the presence of isoflavones in the diet.
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the bovine atp binding cassette transporter abcg2 tyr581ser single nucleotide polymorphism increases milk secretion of the fluoroquinolone Danofloxacin
Drug Metabolism and Disposition, 2013Co-Authors: Jon A Otero, Rebeca Real, J G Prieto, A I Alvarez, A De La Fuente, Margarita M Marques, Gracia MerinoAbstract:The bovine adenosine triphosphate-binding cassette transporter G2 (ABCG2/breast cancer resistance protein) polymorphism Tyr581Ser (Y581S) has recently been shown to increase in vitro transepithelial transport of antibiotics. Since this transporter has been extensively related to the active secretion of drugs into milk, the potential in vivo effect of this polymorphism on secretion of xenobiotics in livestock could have striking consequences for milk production, the dairy industry, and public health. Our purpose was to study the in vivo effect of this polymorphism on the secretion of Danofloxacin, a widely used veterinary antibiotic, into milk. Danofloxacin (1.25 mg/kg) was administered to six Y/Y 581 homozygous and six Y/S 581 heterozygous lactating cows, and plasma and milk samples were collected and analyzed by high-performance liquid chromatography. No differences were found in the pharmacokinetic parameters of Danofloxacin in plasma between the two groups of animals. In contrast, Y/S heterozygous cows showed a 2-fold increase in Danofloxacin levels in milk. In addition, the pharmacokinetic elimination parameters, mean residence time and elimination half-life, were significantly lower in the milk of the animals carrying the Y/S polymorphism. These in vivo results are in agreement with our previously published in vitro data, which showed a greater capacity of the S581 variant in accumulation assays, and demonstrate, for the first time, an important effect of the Y581S single-nucleotide polymorphism on antibiotic secretion into cow milk. These findings could be extended to other ABCG2 substrates, and may be relevant for the treatment of mastitis and for the design of accurate and novel strategies to handle milk residues.
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Inhibition of ABCG2/BCRP transporter by soy isoflavones genistein and daidzein: Effect on plasma and milk levels of Danofloxacin in sheep
Veterinary Journal, 2012Co-Authors: Miriam Perez, Borja Barrera, J G Prieto, Gracia Merino, Jon A Otero, A I AlvarezAbstract:Abstract Danofloxacin is a synthetic fluoroquinolone antibacterial agent and a substrate for ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP). This protein actively extrudes drugs from cells in the intestine, liver, kidney, and other organs, such as the mammary gland. The purpose of this study was to determine whether genistein and daidzein, isoflavones present in soy and known inhibitors of ABCG2, could diminish Danofloxacin secretion into milk. The results obtained from BCRP-transduced MDCK-II cells (Mardin-Darby canine kidney) showed that both isoflavones efficiently inhibited the in vitro transport of the drug. In addition, Danofloxacin transport into milk was studied in Assaf sheep. The experimental design with ewes ( n = 18) included ewes fed with standard forage, soy-enriched forage for 15 days prior to the experiment or standard forage paired with orally administered exogenous genistein and daidzein. The Danofloxacin levels in the milk of ewes in the soy-enriched diet group were decreased. The area under concentration–time curve AUC (0–24 h) was 9.3 ± 4.6 vs. 16.58 ± 4.44 μg h/mL in the standard forage or control group. The plasma levels of Danofloxacin were unmodified. The AUC (0–24 h) milk/plasma ratio decreased by over 50% in the soy-enriched diet group, compared to the control group (4.90 ± 2.65 vs. 9.58 ± 2.17). Exogenous administration of isoflavones did not modify Danofloxacin secretion into milk. This study showed that milk excretion of a specific substrate of BCRP, such as Danofloxacin, can be diminished by the presence of isoflavones in the diet.
Huanzhong Ding - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic/Pharmacodynamic Integration to Evaluate the Changes in Susceptibility of Actinobacillus pleuropneumoniae After Repeated Administration of Danofloxacin
Frontiers in Microbiology, 2018Co-Authors: Longfei Zhang, Zilong Huang, Xiangguang Shen, Zheng Kang, Xiaoyan Gu, Huanzhong DingAbstract:To evaluate the relationship between pharmacokinetic/pharmacodynamic (PK/PD) parameters and changes in susceptibility and resistance frequency of Actinobacillus pleuropneumoniae CVCC 259, a piglet tissue cage infection model was established. After A. pleuropneumoniae populations maintained at 108 CFU/mL in tissue cages, piglets were treated with various concentrations of Danofloxacin once daily for 5 consecutive days by intramuscular injection. Both the concentrations of Danofloxacin and the population of vial cells were calculated. Changes in susceptibility and resistance frequency were monitored. PCR amplification of quinolone resistance-determining regions (QRDRs) and DNA sequencing were performed to identify point mutations in gyrA, gyrB, parC, and parE genes. Furthermore, the susceptibility of mutants to Danofloxacin and enrofloxacin was determined in the presence or absence of reserpine to assess whether the mutants were caused by efflux pumps. The MICs and resistant frequency of A. pleuropneumoniae both increased when Danofloxacin concentrations fluctuated between MIC99 (0.05 μg/mL) and MPC (mutant prevention concentration, 0.4 μg/mL). As for PK/PD parameters, the resistant mutants were selected and enriched when AUC24h/MIC99 ranged from 34.68 to 148.65 h or AUC24h/MPC ranged from 4.33 to 18.58 h. Substitutions of Ser-83→Tyr or Ser-83→Phe in gyrA and Lys-53→Glu in parC were observed. The susceptibility of mutants obtained via Danofloxacin treatment at 1.25 and 2.5 mg/kg were less affected by reserpine. These results demonstrate that maintaining the value of AUC24h/MPC above 18.58 h may produce a desirable antibacterial effect and protect against A. pleuropneumoniae resistance to Danofloxacin.
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pharmacokinetic pharmacodynamic integration to evaluate the changes in susceptibility of actinobacillus pleuropneumoniae after repeated administration of Danofloxacin
Frontiers in Microbiology, 2018Co-Authors: Longfei Zhang, Zilong Huang, Xiangguang Shen, Zheng Kang, Xiaoyan Gu, Huanzhong DingAbstract:To evaluate the relationship between pharmacokinetic/pharmacodynamic (PK/PD) parameters and changes in susceptibility and resistance frequency of Actinobacillus pleuropneumoniae CVCC 259, a piglet tissue cage infection model was established. After A. pleuropneumoniae populations maintained at 108 CFU/mL in tissue cages, piglets were treated with various concentrations of Danofloxacin once daily for 5 consecutive days by intramuscular injection. Both the concentrations of Danofloxacin and the population of vial cells were calculated. Changes in susceptibility and resistance frequency were monitored. PCR amplification of quinolone resistance-determining regions (QRDRs) and DNA sequencing were performed to identify point mutations in gyrA, gyrB, parC, and parE genes. Furthermore, the susceptibility of mutants to Danofloxacin and enrofloxacin was determined in the presence or absence of reserpine to assess whether the mutants were caused by efflux pumps. The MICs and resistant frequency of A. pleuropneumoniae both increased when Danofloxacin concentrations fluctuated between MIC99 (0.05 μg/mL) and MPC (mutant prevention concentration, 0.4 μg/mL). As for PK/PD parameters, the resistant mutants were selected and enriched when AUC24h/MIC99 ranged from 34.68 to 148.65 h or AUC24h/MPC ranged from 4.33 to 18.58 h. Substitutions of Ser-83→Tyr or Ser-83→Phe in gyrA and Lys-53→Glu in parC were observed. The susceptibility of mutants obtained via Danofloxacin treatment at 1.25 and 2.5 mg/kg were less affected by reserpine. These results demonstrate that maintaining the value of AUC24h/MPC above 18.58 h may produce a desirable antibacterial effect and protect against A. pleuropneumoniae resistance to Danofloxacin.
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relationship between Danofloxacin pk pd parameters and emergence and mechanism of resistance of mycoplasma gallisepticum in in vitro model
PLOS ONE, 2018Co-Authors: Nan Zhang, Yuzhi Wu, Zilong Huang, Longfei Zhang, Xiangguang Shen, Hongxia Jiang, Chuanzhen Zhang, Huanzhong DingAbstract:Mycoplasma gallisepticum is a serious pathogen for poultry that causes chronic respiratory disease in chickens. Increased embryonic mortality, as well as reduced weight gain and egg production have been found in infected chickens, which can lead to considerable economic losses in poultry production. Increased antibiotic resistance compromises the use of tetracyclines, macrolides and quinolones in the farm environment. In the present study, Danofloxacin concentrations were simulated below the MIC99, between the MIC99 and MPC (the mutant prevention concentration), and above the MPC in an in vitro dynamic model against M. gallisepticum. The relationship between the simulated Danofloxacin pharmacokinetics, pharmacodynamics (PK/PD) parameters and development of resistance for M. gallisepticum was explored based on the available data obtained from various dosing regimens in the in vitro model. Danofloxacin concentration, counts of viable cell and susceptibility were determined during the experiment. The mutations in gyrA, gyrB, parC and parE as well as efflux pumps were examined. The MIC of Danofloxacin against M. gallisepticum was increased when drug concentrations were between the lower and upper boundaries of the mutant selection window. The upper boundary of the selection window in vitro was estimated as a Cmax/MPC value of 1. The lower boundary was estimated as Cmax/MPC value of 0.05. Both in terms of the MIC and resistance frequency, M. gallisepticum resistance was developed when Danofloxacin concentrations fell inside the mutant selection window (ratios of Cmax to MPC between 0.05 and 1). The single mutation in gyrA (Ser-83→Arg) was found in all mutants, while double mutations in gyrA and parC (Ala-64→Ser) were observed only in the mutant with the highest MIC. In addition, no change of susceptibility in the mutants was observed in the presence of reserpine and carbonyl cyanide 3-chlorophenylhydrazone (CCCP). This suggested that ATP-binding cassette superfamily (ABC transporter) and major facilitator superfamily (MFS transporter) did not play a role in Danofloxacin efflux.
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the pk pd relationship and resistance development of Danofloxacin against mycoplasma gallisepticum in an in vivo infection model
Frontiers in Microbiology, 2017Co-Authors: Nan Zhang, Yuzhi Wu, Zilong Huang, Longfei Zhang, Xiangguang Shen, Hongxia Jiang, Huanzhong DingAbstract:Mycoplasma gallisepticum is the causative agent of chronic respiratory disease (CRD), a prevalent disease of poultry, which is responsible for significant economic losses in farms. Although several antimicrobial agents are currently recommended for the treatment and prevention of M. gallisepticum infections, investigations of M. gallisepticum have been hampered by their fastidious growth requirements and slow growth rate. As such, little work has been conducted concerning the PK/PD relationship and mechanisms of antibiotic resistance between antimicrobials against M. gallisepticum. In the present study, Danofloxacin was orally administrated to the infected chickens once daily for 3 days by an established in vivo M. gallisepticum infection model. Not only the concentrations of Danofloxacin in plasma and lung tissues were analyzed, but also the counting of viable cells and changes in antimicrobial susceptibility in air sac and lung were determined. The PK and PD data were fitted by WinNonlin to evaluate the PK/PD interactions of Danofloxacin against M. gallisepticum. PCR amplification of quinolone resistance determining regions (QRDRs) and DNA sequencing were performed to identify point mutations in gyrA, gyrB, parC and parE of the selected resistant mutant strains. In addition, susceptibility of enrofloxacin, ofloxacin, levofloxacin, gatifloxacin and norfloxacin against these mutant strains were also determined. The PK profiles indicated that Danofloxacin concentration in the lung tissues was higher than plasma. Mycoplasmacidal activity was achieved when infected chickens were exposed to Danofloxacin at the dose group above 2.5 mg/kg. The ratios of AUC24/MIC (the area under the concentration-time curve over 24 h divided by the MIC) for 2 log10 (CFU) and 3 log10 (CFU) reduction were 31.97 and 97.98 L·h/kg, respectively. Substitutions of Ser-83→Arg or Glu-87→Gly in gyrA; Glu-84→Lys in parC were observed in the resistant mutant strains that were selected from the dose group of 1 and 2.5 mg/kg. MICs of Danofloxacin, enrofloxacin, ofloxacin, levofloxacin, gatifloxacin and norfloxacin against the resistant mutant strains with a single mutation in position-83 were higher than that with a single mutation in position-87. These findings suggested that danfloxacin may be therapeutically effective to treat M. gallisepticum infection in chickens if administered at a dosage of 5.5 mg/kg once
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determination of the mutant selection window and evaluation of the killing of mycoplasma gallisepticum by Danofloxacin doxycycline tilmicosin tylvalosin and valnemulin
PLOS ONE, 2017Co-Authors: Nan Zhang, Yuzhi Wu, Zilong Huang, Xiangguang Shen, Hongxia Jiang, Xiaoyan Gu, Xiaomei Ye, Huanzhong DingAbstract:Mycoplasma gallisepticum is a common etiological cause of a chronic respiratory disease in chickens; its increasing antimicrobial resistance compromises the use of tetracyclines, macrolides and quinolones in the farm environment. Mutant selection window (MSW) determination was used to investigate the propensity for future resistance induction by Danofloxacin, doxycycline, tilmicosin, tylvalosin and valnemulin. Killing of M. gallisepticum strain S6 by these antimicrobials was also studied by incubating M. gallisepticum into medium containing the compounds at the minimal concentration that inhibits colony formation by 99% (MIC99) and the mutant prevention concentration (MPC). Based on the morphology and colony numbers of M. gallisepticum on agar plates, the four kinds of sera in the order of the applicability for culturing M. gallisepticum were swine serum > horse serum > bovine serum > mixed serum. The MPC/MIC99 values for each agent were as follows: Danofloxacin > tilmicosin > tylvalosin > doxycycline > valnemulin. MPC generated more rapid and greater magnitude killing than MIC99 against M. gallisepticum. Under exposure of 105–109 CFU/mL at MPC drug levels, valnemulin had the slowest rate of reduction in viable organisms and Danofloxacin had the highest rate of reduction.
T G Rowan - One of the best experts on this subject based on the ideXlab platform.
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Danofloxacin advocin reduces the spread of contagious bovine pleuropneumonia to healthy in contact cattle
Research in Veterinary Science, 2006Co-Authors: Otto J B Huebschle, T G Rowan, Kevin Godinho, Roger D Ayling, Obed Lukhele, Georgina Tjipurazaire, R A J NicholasAbstract:Abstract Contagious bovine pleuropneumonia (CBPP), caused by Mycoplasma mycoides subsp. mycoides SC ( Mmm SC), is one of the most important diseases of cattle in Sub-Saharan Africa. The live T1/44 vaccine is normally used for its control but produces only transient protection and gives rise to adverse reactions. The present study evaluated the efficacy of Danofloxacin (2.5% Advocin™, Pfizer Ltd.) for the treatment of naturally infected cattle and in the prevention of CBPP transmission to in-contact cattle. Adult cattle, taken from a natural outbreak, were placed into two groups of 10 animals and kept on a research farm in paddocks 50 m apart. One group was treated with 2.5 mg/kg Danofloxacin on days 0, 1 and 2; the other group were saline treated. On day 2, 10 CBPP-free, seronegative cattle were placed in contact with each of the two groups. All cattle were monitored for 3.5 months. No differences were seen in clinical improvement of the CBPP-affected cattle treated with Danofloxacin compared with the untreated CBPP-affected cattle with approximately half of each group being withdrawn because of CBPP or showing CBPP lesions at post mortem examination. Clinical scores of the two groups were also similar. However cattle kept in contact with the Danofloxacin-treated CBPP-affected animals showed significantly fewer lesions, less mortality and fewer animals were seropositive ( P P Mmm SC was also isolated from fewer contact controls kept with the treated group. These findings could have important implications for the control of CBPP in Africa.
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effect of Danofloxacin advocin a180 on goats affected with contagious caprine pleuropneumonia
Tropical Animal Health and Production, 2006Co-Authors: U Ozdemir, T G Rowan, G R Loria, Kevin Godinho, R Samson, Colin P Churchward, Roger D Ayling, R A J NicholasAbstract:The efficacy of Danofloxacin (Advocin® A180) was evaluated for the treatment of contagious caprine pleuropneumonia (CCPP) caused by Mycoplasma capricolum subsp. capripneumoniae. Ten healthy Angora goats, confirmed free of CCPP, were exposed to clinically affected animals from a natural outbreak in Thrace, Turkey. After 14 days exposure, 8 goats showed pyrexia (≥41°C). Shortly after, the Angora goats were divided randomly into two groups. Five of these were injected with Danofloxacin (6 mg/kg subcutaneously), which was repeated after 48 h; the five remaining animals received saline. Goats were monitored clinically and blood samples were collected for serology. Animals with severe disease were withdrawn from the trial. Goats completing the study were euthanized at day 42. Lung tissue and bronchial fluid were collected for mycoplasma isolation. All Danofloxacin-treated goats showed resolution of clinical disease by the end of the trial. Two saline-treated goats failed to complete the study owing to CCPP. Danofloxacin-treated goats showed fewer lung lesions and had significantly lower combined clinical scores than saline controls (p < 0.001). Danofloxacin was found to be highly effective in the treatment of CCPP in goats.
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Effect of Danofloxacin (Advocin A180) on goats affected with contagious caprine pleuropneumonia.
Tropical animal health and production, 2006Co-Authors: U Ozdemir, T G Rowan, G R Loria, Kevin Godinho, R Samson, Colin P Churchward, Roger D Ayling, R A J NicholasAbstract:The efficacy of Danofloxacin (Advocin A180) was evaluated for the treatment of contagious caprine pleuropneumonia (CCPP) caused by Mycoplasma capricolum subsp. capripneumoniae. Ten healthy Angora goats, confirmed free of CCPP, were exposed to clinically affected animals from a natural outbreak in Thrace, Turkey. After 14 days exposure, 8 goats showed pyrexia ( > or = 41 degrees C). Shortly after, the Angora goats were divided randomly into two groups. Five of these were injected with Danofloxacin (6 mg/kg subcutaneously), which was repeated after 48 h; the five remaining animals received saline. Goats were monitored clinically and blood samples were collected for serology. Animals with severe disease were withdrawn from the trial. Goats completing the study were euthanized at day 42. Lung tissue and bronchial fluid were collected for mycoplasma isolation. All Danofloxacin-treated goats showed resolution of clinical disease by the end of the trial. Two saline-treated goats failed to complete the study owing to CCPP. Danofloxacin-treated goats showed fewer lung lesions and had significantly lower combined clinical scores than saline controls (p < 0.001). Danofloxacin was found to be highly effective in the treatment of CCPP in goats.
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Effect of Danofloxacin (Advocin A180) on goats affected with contagious caprine pleuropneumonia
Tropical Animal Health and Production, 2006Co-Authors: U Ozdemir, T G Rowan, G R Loria, Kevin Godinho, R Samson, Colin P Churchward, Roger D Ayling, R A J NicholasAbstract:The efficacy of Danofloxacin (Advocin^® A180) was evaluated for the treatment of contagious caprine pleuropneumonia (CCPP) caused by Mycoplasma capricolum subsp. capripneumoniae . Ten healthy Angora goats, confirmed free of CCPP, were exposed to clinically affected animals from a natural outbreak in Thrace, Turkey. After 14 days exposure, 8 goats showed pyrexia (≥41^°C). Shortly after, the Angora goats were divided randomly into two groups. Five of these were injected with Danofloxacin (6 mg/kg subcutaneously), which was repeated after 48 h; the five remaining animals received saline. Goats were monitored clinically and blood samples were collected for serology. Animals with severe disease were withdrawn from the trial. Goats completing the study were euthanized at day 42. Lung tissue and bronchial fluid were collected for mycoplasma isolation. All Danofloxacin-treated goats showed resolution of clinical disease by the end of the trial. Two saline-treated goats failed to complete the study owing to CCPP. Danofloxacin-treated goats showed fewer lung lesions and had significantly lower combined clinical scores than saline controls ( p
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efficacy of Danofloxacin in the treatment of respiratory disease in european cattle
Veterinary Record, 2004Co-Authors: T G Rowan, C J Giles, P Sarasola, S J Sunderland, D G SmithAbstract:The efficacy of an injectable formulation of Danofloxacin (180 mg/ml) in the treatment of naturally occurring bovine respiratory disease was evaluated in field studies on farms in France, Ireland and the United Kingdom. Cattle aged one week to 15 months with clinical respiratory disease were randomly allocated to treatment with 6 mg/kg Danofloxacin or 10 mg/kg tilmicosin, administered by a single subcutaneous injection on day 0. A second injection of Danofloxacin was administered on day 2, only if predefined clinical criteria were met. Mannheimia haemolytica , Pasteurella muftocida and Haemophilus somnus were isolated from pretreatment nasopharyngeal swabs taken on all the farms. After the treatment, there was a more rapid improvement in the clinical response of the 178 animals treated with Danofloxacin by day 2 (P<0-01) than in the 90 treated with tilmicosin. For both treatments, there were similar significant (P<0-001) reductions in the mean rectal temperature and severity of clinical signs of abnormal respiration and depression, on days 4 and 10 compared with day 0; 78.1 per cent of the animals treated with Danofloxacin and 78.5 per cent of those treated with tilmicosin completed the studies. Danofloxacin 18 per cent was clinically safe and as effective as tilmicosin in the treatment of bovine respiratory disease.
Nan Zhang - One of the best experts on this subject based on the ideXlab platform.
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relationship between Danofloxacin pk pd parameters and emergence and mechanism of resistance of mycoplasma gallisepticum in in vitro model
PLOS ONE, 2018Co-Authors: Nan Zhang, Yuzhi Wu, Zilong Huang, Longfei Zhang, Xiangguang Shen, Hongxia Jiang, Chuanzhen Zhang, Huanzhong DingAbstract:Mycoplasma gallisepticum is a serious pathogen for poultry that causes chronic respiratory disease in chickens. Increased embryonic mortality, as well as reduced weight gain and egg production have been found in infected chickens, which can lead to considerable economic losses in poultry production. Increased antibiotic resistance compromises the use of tetracyclines, macrolides and quinolones in the farm environment. In the present study, Danofloxacin concentrations were simulated below the MIC99, between the MIC99 and MPC (the mutant prevention concentration), and above the MPC in an in vitro dynamic model against M. gallisepticum. The relationship between the simulated Danofloxacin pharmacokinetics, pharmacodynamics (PK/PD) parameters and development of resistance for M. gallisepticum was explored based on the available data obtained from various dosing regimens in the in vitro model. Danofloxacin concentration, counts of viable cell and susceptibility were determined during the experiment. The mutations in gyrA, gyrB, parC and parE as well as efflux pumps were examined. The MIC of Danofloxacin against M. gallisepticum was increased when drug concentrations were between the lower and upper boundaries of the mutant selection window. The upper boundary of the selection window in vitro was estimated as a Cmax/MPC value of 1. The lower boundary was estimated as Cmax/MPC value of 0.05. Both in terms of the MIC and resistance frequency, M. gallisepticum resistance was developed when Danofloxacin concentrations fell inside the mutant selection window (ratios of Cmax to MPC between 0.05 and 1). The single mutation in gyrA (Ser-83→Arg) was found in all mutants, while double mutations in gyrA and parC (Ala-64→Ser) were observed only in the mutant with the highest MIC. In addition, no change of susceptibility in the mutants was observed in the presence of reserpine and carbonyl cyanide 3-chlorophenylhydrazone (CCCP). This suggested that ATP-binding cassette superfamily (ABC transporter) and major facilitator superfamily (MFS transporter) did not play a role in Danofloxacin efflux.
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the pk pd relationship and resistance development of Danofloxacin against mycoplasma gallisepticum in an in vivo infection model
Frontiers in Microbiology, 2017Co-Authors: Nan Zhang, Yuzhi Wu, Zilong Huang, Longfei Zhang, Xiangguang Shen, Hongxia Jiang, Huanzhong DingAbstract:Mycoplasma gallisepticum is the causative agent of chronic respiratory disease (CRD), a prevalent disease of poultry, which is responsible for significant economic losses in farms. Although several antimicrobial agents are currently recommended for the treatment and prevention of M. gallisepticum infections, investigations of M. gallisepticum have been hampered by their fastidious growth requirements and slow growth rate. As such, little work has been conducted concerning the PK/PD relationship and mechanisms of antibiotic resistance between antimicrobials against M. gallisepticum. In the present study, Danofloxacin was orally administrated to the infected chickens once daily for 3 days by an established in vivo M. gallisepticum infection model. Not only the concentrations of Danofloxacin in plasma and lung tissues were analyzed, but also the counting of viable cells and changes in antimicrobial susceptibility in air sac and lung were determined. The PK and PD data were fitted by WinNonlin to evaluate the PK/PD interactions of Danofloxacin against M. gallisepticum. PCR amplification of quinolone resistance determining regions (QRDRs) and DNA sequencing were performed to identify point mutations in gyrA, gyrB, parC and parE of the selected resistant mutant strains. In addition, susceptibility of enrofloxacin, ofloxacin, levofloxacin, gatifloxacin and norfloxacin against these mutant strains were also determined. The PK profiles indicated that Danofloxacin concentration in the lung tissues was higher than plasma. Mycoplasmacidal activity was achieved when infected chickens were exposed to Danofloxacin at the dose group above 2.5 mg/kg. The ratios of AUC24/MIC (the area under the concentration-time curve over 24 h divided by the MIC) for 2 log10 (CFU) and 3 log10 (CFU) reduction were 31.97 and 97.98 L·h/kg, respectively. Substitutions of Ser-83→Arg or Glu-87→Gly in gyrA; Glu-84→Lys in parC were observed in the resistant mutant strains that were selected from the dose group of 1 and 2.5 mg/kg. MICs of Danofloxacin, enrofloxacin, ofloxacin, levofloxacin, gatifloxacin and norfloxacin against the resistant mutant strains with a single mutation in position-83 were higher than that with a single mutation in position-87. These findings suggested that danfloxacin may be therapeutically effective to treat M. gallisepticum infection in chickens if administered at a dosage of 5.5 mg/kg once
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determination of the mutant selection window and evaluation of the killing of mycoplasma gallisepticum by Danofloxacin doxycycline tilmicosin tylvalosin and valnemulin
PLOS ONE, 2017Co-Authors: Nan Zhang, Yuzhi Wu, Zilong Huang, Xiangguang Shen, Hongxia Jiang, Xiaoyan Gu, Xiaomei Ye, Huanzhong DingAbstract:Mycoplasma gallisepticum is a common etiological cause of a chronic respiratory disease in chickens; its increasing antimicrobial resistance compromises the use of tetracyclines, macrolides and quinolones in the farm environment. Mutant selection window (MSW) determination was used to investigate the propensity for future resistance induction by Danofloxacin, doxycycline, tilmicosin, tylvalosin and valnemulin. Killing of M. gallisepticum strain S6 by these antimicrobials was also studied by incubating M. gallisepticum into medium containing the compounds at the minimal concentration that inhibits colony formation by 99% (MIC99) and the mutant prevention concentration (MPC). Based on the morphology and colony numbers of M. gallisepticum on agar plates, the four kinds of sera in the order of the applicability for culturing M. gallisepticum were swine serum > horse serum > bovine serum > mixed serum. The MPC/MIC99 values for each agent were as follows: Danofloxacin > tilmicosin > tylvalosin > doxycycline > valnemulin. MPC generated more rapid and greater magnitude killing than MIC99 against M. gallisepticum. Under exposure of 105–109 CFU/mL at MPC drug levels, valnemulin had the slowest rate of reduction in viable organisms and Danofloxacin had the highest rate of reduction.
Borja Barrera - One of the best experts on this subject based on the ideXlab platform.
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short communication the gain of function y581s polymorphism of the abcg2 transporter increases secretion into milk of Danofloxacin at the therapeutic dose for mastitis treatment
Journal of Dairy Science, 2015Co-Authors: Jon A Otero, Borja Barrera, J G Prieto, A I Alvarez, A De La Fuente, Margarita M Marques, Gracia MerinoAbstract:Abstract The ATP-binding cassette transporter ABCG2 restricts the exposure of certain drugs and natural compounds in different tissues and organs. Its expression in the mammary gland is induced during lactation and is responsible for the active secretion of many compounds into milk, including antimicrobial agents. This particular function of ABCG2 may affect drug efficacy against mastitis and the potential presence of drug residues in the milk. Previous in vitro and in vivo studies showed increased transport of several compounds, including fluoroquinolones, by the bovine ABCG2 Y581S polymorphism. Our main purpose was to study the potential effect of this bovine ABCG2 polymorphism on the secretion into milk of the antimicrobial Danofloxacin administered at the therapeutic dose of 6mg/kg used for mastitis treatment. In addition, the effect of this polymorphism on the relative mRNA and protein levels of ABCG2 by quantitative real-time PCR and Western blot were studied. Danofloxacin 18% (6mg/kg) was administered to 6 Y/Y homozygous and 5 Y/S heterozygous cows. Danofloxacin levels in milk and milk-to-plasma concentration ratios were almost 1.5- and 2-fold higher, respectively, in Y/S cows compared with the Y/Y cows, showing a higher capacity of this variant to transport Danofloxacin into milk. Furthermore, the higher activity of this polymorphism is not linked to higher ABCG2 mRNA or protein levels. These results demonstrate the relevant effect of the Y581S polymorphism of the bovine ABCG2 transporter in the secretion into milk of Danofloxacin after administration of 6mg/kg, with potentially important consequences for mastitis treatment and for milk residue handling.
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effects of triclabendazole on secretion of Danofloxacin and moxidectin into the milk of sheep role of triclabendazole metabolites as inhibitors of the ruminant abcg2 transporter
Veterinary Journal, 2013Co-Authors: Borja Barrera, Rebeca Real, L Gonzalezlobato, Jon A Otero, J G Prieto, A I Alvarez, Gracia MerinoAbstract:Abstract ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP) mediates drug–drug interactions that affect the secretion of drugs into milk. The aims of this study were: (1) to determine whether the major plasma metabolites of the flukicide triclabendazole (TCBZ), triclabendazole sulfoxide (TCBZSO) and triclabendazole sulfone (TCBZSO 2 ), inhibit ovine and bovine ABCG2 and its Y581S variant in vitro, and (2) to examine whether coadministration of TCBZ with the ABCG2 substrates Danofloxacin (a fluoroquinolone) and moxidectin (a milbemycin) affects the secretion of these drugs into the milk of sheep. TCBZSO and TCBZSO 2 inhibited ruminant ABCG2 in vitro by reversing the reduced mitoxantrone accumulation and reducing basal to apical transport of nitrofurantoin in cells transduced with bovine variants (S581 and Y581) and the ovine variant of ABCG2. Coadministration of TCBZ with moxidectin or Danofloxacin to sheep resulted in significantly reduced levels of moxidectin, but not Danofloxacin, in the milk of TCBZ-treated sheep compared to sheep administered moxidectin or Danofloxacin alone. The milk area under concentration time curve (AUC 0–48 h) was 2.99 ± 1.41 μg h/mL in the group treated with TCBZ and moxidectin, and 7.75 ± 3.58 μg h/mL in the group treated with moxidectin alone. The AUC (0–48 h) milk/plasma ratio was 37% lower in the group treated with TCBZ and moxidectin (7.34 ± 1.51) than in the group treated with moxidectin alone (11.68 ± 3.61). TCBZ metabolites appear to inhibit ruminant ABCG2 and affect the secretion of ABCG2 substrates into milk of sheep.
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inhibition of abcg2 bcrp transporter by soy isoflavones genistein and daidzein effect on plasma and milk levels of Danofloxacin in sheep
Veterinary Journal, 2013Co-Authors: Miriam Perez, Borja Barrera, Gracia Merino, Jon A Otero, J G Prieto, A I AlvarezAbstract:Abstract Danofloxacin is a synthetic fluoroquinolone antibacterial agent and a substrate for ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP). This protein actively extrudes drugs from cells in the intestine, liver, kidney, and other organs, such as the mammary gland. The purpose of this study was to determine whether genistein and daidzein, isoflavones present in soy and known inhibitors of ABCG2, could diminish Danofloxacin secretion into milk. The results obtained from BCRP-transduced MDCK-II cells (Mardin-Darby canine kidney) showed that both isoflavones efficiently inhibited the in vitro transport of the drug. In addition, Danofloxacin transport into milk was studied in Assaf sheep. The experimental design with ewes ( n = 18) included ewes fed with standard forage, soy-enriched forage for 15 days prior to the experiment or standard forage paired with orally administered exogenous genistein and daidzein. The Danofloxacin levels in the milk of ewes in the soy-enriched diet group were decreased. The area under concentration–time curve AUC (0–24 h) was 9.3 ± 4.6 vs. 16.58 ± 4.44 μg h/mL in the standard forage or control group. The plasma levels of Danofloxacin were unmodified. The AUC (0–24 h) milk/plasma ratio decreased by over 50% in the soy-enriched diet group, compared to the control group (4.90 ± 2.65 vs. 9.58 ± 2.17). Exogenous administration of isoflavones did not modify Danofloxacin secretion into milk. This study showed that milk excretion of a specific substrate of BCRP, such as Danofloxacin, can be diminished by the presence of isoflavones in the diet.
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Inhibition of ABCG2/BCRP transporter by soy isoflavones genistein and daidzein: Effect on plasma and milk levels of Danofloxacin in sheep
Veterinary Journal, 2012Co-Authors: Miriam Perez, Borja Barrera, J G Prieto, Gracia Merino, Jon A Otero, A I AlvarezAbstract:Abstract Danofloxacin is a synthetic fluoroquinolone antibacterial agent and a substrate for ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP). This protein actively extrudes drugs from cells in the intestine, liver, kidney, and other organs, such as the mammary gland. The purpose of this study was to determine whether genistein and daidzein, isoflavones present in soy and known inhibitors of ABCG2, could diminish Danofloxacin secretion into milk. The results obtained from BCRP-transduced MDCK-II cells (Mardin-Darby canine kidney) showed that both isoflavones efficiently inhibited the in vitro transport of the drug. In addition, Danofloxacin transport into milk was studied in Assaf sheep. The experimental design with ewes ( n = 18) included ewes fed with standard forage, soy-enriched forage for 15 days prior to the experiment or standard forage paired with orally administered exogenous genistein and daidzein. The Danofloxacin levels in the milk of ewes in the soy-enriched diet group were decreased. The area under concentration–time curve AUC (0–24 h) was 9.3 ± 4.6 vs. 16.58 ± 4.44 μg h/mL in the standard forage or control group. The plasma levels of Danofloxacin were unmodified. The AUC (0–24 h) milk/plasma ratio decreased by over 50% in the soy-enriched diet group, compared to the control group (4.90 ± 2.65 vs. 9.58 ± 2.17). Exogenous administration of isoflavones did not modify Danofloxacin secretion into milk. This study showed that milk excretion of a specific substrate of BCRP, such as Danofloxacin, can be diminished by the presence of isoflavones in the diet.
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involvement of breast cancer resistance protein bcrp abcg2 in the secretion of Danofloxacin into milk interaction with ivermectin
Journal of Veterinary Pharmacology and Therapeutics, 2011Co-Authors: Rebeca Real, Estefania Egido, Miriam Perez, L Gonzalezlobato, Borja Barrera, J G Prieto, A I Alvarez, Gracia MerinoAbstract:Real, R., Egido, E., Perez, M., Gonzalez-Lobato, L., Barrera, B., Prieto, J. G., Alvarez, A.I., Merino, G. Involvement of breast cancer resistance protein (BCRP/ABCG2) in the secretion of Danofloxacin into milk: interaction with ivermectin. J. vet. Pharmacol. Therap.34, 313–321. Danofloxacin, a veterinary fluoroquinolone antimicrobial drug, is actively secreted into milk by an as yet unknown mechanism. One of the main determinants of active drug secretion into milk is the transporter (BCRP/ABCG2). The main purpose was to determine whether Danofloxacin is an in vitro substrate for Bcrp1/BCRP and to assess its involvement in Danofloxacin secretion into milk. In addition, the role of potential drug–drug interactions in this process was assessed using ivermectin. Danofloxacin was transported in vitro by Bcrp1/BCRP, and ivermectin efficiently blocked this transport. Experiments with Bcrp1−/− mice showed no evidence of the involvement of Bcrp1 in plasma pharmacokinetics of Danofloxacin. However, the milk concentration and milk-to-plasma ratio of Danofloxacin were almost twofold higher in wild-type compared with Bcrp1−/− mice. The in vivo interaction with ivermectin was studied in sheep after co-administration of Danofloxacin (1.25 mg/kg, i.m.) and ivermectin (0.2 mg/kg, s.c.). Ivermectin had no significant effect on the plasma levels of Danofloxacin but significantly decreased Danofloxacin concentrations in milk by almost 40%. Concomitant administration of multiple drugs, often used in veterinary therapy, may not only affect their pharmacological activity but also their secretion into milk, because of potential drug–drug interactions mediated by BCRP.
