ABSTRACT
Certain dog breeds, especially Collies, are observed to exhibit neurotoxicity to avermectin drugs, which are P-glycoprotein (P-gp) substrates. This neurotoxicity is due to an ABCB1 gene mutation (ABCB1-1Δ) that results in non-functional P-gp expression. A developed Abcb1a knock-in/Abcb1b knock-out mouse model expressing the ABCB1-1Δ canine gene was previously reported and mice exhibited sensitivity upon ivermectin administration. Here, model and wild-type mice were administered P-gp substrates doramectin, moxidectin, and digoxin. While knock-in/knock-out mice exhibited ataxia, lethargy and tremor, wild-type mice remained unaffected. In addition, no neurotoxic clinical signs were observed in either mouse type administered domperidone, a P-gp substrate with no reported neurotoxicity in ABCB1-1Δ Collies. Overall, neurotoxic signs displayed by model mice closely paralleled those observed in ivermectin-sensitive Collies. This model can be used to identify toxic P-gp substrates with altered safety in dog populations and may reduce dog use in safety studies that are part of the drug approval process.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , ATP Binding Cassette Transporter, Subfamily B/genetics , Anti-Infective Agents/toxicity , Brain/drug effects , Digoxin/toxicity , Ivermectin/analogs & derivatives , Macrolides/toxicity , ATP Binding Cassette Transporter, Subfamily B/physiology , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Animals , Disease Models, Animal , Dog Diseases/chemically induced , Dog Diseases/drug therapy , Dogs , Domperidone/toxicity , Female , Ivermectin/toxicity , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutagenesis, Insertional/genetics , Mutagenesis, Insertional/methodsABSTRACT
Sulfonamides are among the oldest, but still effective, antimicrobial veterinary medicines. In steers and dairy cows, the sulfonamides are effective in the treatment of respiratory disease and general infections. Sulfadimethoxine (SDM) has been approved by US Food and Drug Administration (FDA) for use in steers and dairy cows with a tolerance of 100 ng/g (ppb) in edible tissues and 10 ppb in milk. The detection of SDM residue above tolerance in the animal slaughtered for food process will result in the whole carcass being discarded. This report describes a comprehensive depletion study of SDM (and its main metabolite) in plasma, urine, oral fluid, kidney, and liver. In this study, nine steers were injected intravenously with the approved dose of SDM; the loading dose was 55 mg/kg, followed by 27.5 mg/kg dose at 24 h and again at 48 h. Fluids (blood, urine, and saliva) and tissue (liver and kidney) samples were collected at intervals after the last dose of SMD. The combination of laparoscopic serial sampling technique with the liquid chromatography/mass spectrometry method provided the data to establish the tissue/fluid correlation in the depletion of SMD. A strong correlation and linearity of the log-scale concentration over time in the depletion stage has been confirmed for kidney, liver, and plasma.
Subject(s)
Anti-Infective Agents/pharmacokinetics , Body Fluids/metabolism , Kidney/metabolism , Liver/metabolism , Sulfadimethoxine/pharmacokinetics , Animals , Anti-Infective Agents/analysis , Anti-Infective Agents/blood , Anti-Infective Agents/urine , Biopsy/veterinary , Body Fluids/chemistry , Cattle , Female , Injections, Intravenous/veterinary , Kidney/chemistry , Liver/chemistry , Male , Sulfadimethoxine/analysis , Sulfadimethoxine/blood , Sulfadimethoxine/urineABSTRACT
A novel method has been developed for the extraction and simultaneous separation and quantitation of key arachidonate metabolites and platelet activating factor (PAF) from plasma samples of limited size. Aqueous solutions of these metabolites were added onto a solid phase C-18 cartridge and arachidonate metabolites and PAF were eluted, successively, with acetonitrile-methanol (85:15, v/v), followed by 100% methanol. Arachidonate metabolites (first eluate) were fractionated by C-18 reverse-phase high-performance liquid chromatography using a program designed for the resolution of 31 arachidonate metabolites (3-min separation). The fractions were collected and assayed by radioimmunoassay or radiography, if radioactively labeled. Two internal standards were added to each sample, 15-hydroxyeicosadienoic acid (detected at 235 nm) to determine gradient shifts and [1-14C]eicosatrienoic acid to estimate the recoveries of arachidonate metabolites at any stage of the process. This method was developed to answer specific questions concerning the mode of action of Staphylococcus aureus enterotoxin B (SEB). Plasma samples from mice challenged with SEB were analyzed and major differences were seen in 5-lipoxygenase metabolites. Low doses of SEB vs saline stimulated 5-hydroxyeicosatetraenoic acid production, while high doses of SEB stimulated leukotriene D4 production.
Subject(s)
Arachidonic Acid/blood , Enterotoxins/pharmacology , Platelet Activating Factor/isolation & purification , Platelet Activating Factor/metabolism , Staphylococcus aureus , Animals , Chemistry Techniques, Analytical/methods , Chromatography, High Pressure Liquid , Hydroxyeicosatetraenoic Acids/blood , Hydroxyeicosatetraenoic Acids/isolation & purification , Leukotrienes/blood , Leukotrienes/isolation & purification , Male , Mice , Mice, Inbred ICR , Microchemistry/methods , SpectrophotometryABSTRACT
Ten volatile compounds derived from the cephalic glands of the fire beeTrigona (Oxytrigona)mellicolor were bioassayed for possible allomonal activities facilitating nest plundering. Two diketones, (E)-3-heptene-2,5-dione and (E)-3-nonene-2,5-dione, caused the honeybeeApis mellifera to display avoidance behavior and reduced defensive behavior. These diketones are produced in relatively large quantities in fire-bee cephalic glands.
ABSTRACT
Plants were obtained from protoplasts of shoot cultures of potato (Solarium tuberosum L. cv. 'Maris Bard') and from in situ calluses upon plants of cv. 'Majestic'. None of the protoplast-derived plants resembled each other in all of ten morphological characteristics scored and only one resembled the parental 'Maris Bard' type. As there were a number of plants regenerated from each of ten protoplast-derived calluses it is concluded that variation arose after protoplast isolation during the cell culture phase. Plants regenerated from in situ calluses of cv. 'Majestic' were quite uniform. Reported cases of variation and uniformity from cultured potato tissues are discussed. It is concluded that the variation is not a consequence of using protoplasts and that the expression or induction of variation is controllable.
