1,721,013 research outputs found
Single-Dose Pharmacokinetics of Piperacillin/Tazobactam in Hispaniolan Amazon Parrots ( Amazona ventralis )
No full textTo determine the pharmacokinetics of piperacillin/tazobactam in Hispaniolan Amazon parrots ( Amazona ventralis ), 8 healthy adult parrots of both sexes were used in a 2-part study. In a pilot study, piperacillin (87 mg/kg) in combination with tazobactam (11 mg/kg) was administered intramuscularly (IM) to 2 birds, and blood samples were obtained at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours after administration. Based on the results obtained, a main study was done in which piperacillin/tazobactam was administered at 2 different doses. In 3 birds, the initial dose of piperacillin (87 mg/kg)/tazobactam (11 mg/kg) IM was administered, and in 3 birds, the dose was doubled to piperacillin (174 mg/kg)/tazobactam (22 mg/kg) IM. In all 6 birds, blood samples were obtained at 0, 5, 15, and 30 minutes and at 1, 1.5, 2, 2.5, 3, and 4 hours after administration. Quantification of plasma piperacillin and tazobactam concentrations was determined by validated liquid chromatography-mass spectrometry assay. Pharmacokinetic parameters were determined by noncompartmental analysis. After intramuscular administration, the mean ± standard error values of T1/2 (h) was 0.52 ± 0.05 and 0.32 ± 0.07, Tmax (h) was 0.28 ± 0.09 and 0.25 ± 0.10, Cmax (μg/mL) was 86.34 ± 20.62 and 9.03 ± 2.88, and Cmax/dose was 0.99 ± 0.24 and 0.83 ± 0.26 for piperacillin (87 mg/kg) and tazobactam (11 mg/kg), respectively. When the doses were doubled, the T1/2 (h) was 0.65 ± 0.08 and 0.34 ± 0.02, Tmax (h) was 0.28 ± 0.12 and 0.14 ± 0.06, Cmax (μg/mL) was 233.0 ± 6.08 and 22.13 ± 2.35, and Cmax/dose was 1.34 ± 0.03 and 1.02 ± 0.11 for piperacillin and tazobactam, respectively. Results indicate that piperacillin is rapidly absorbed and reaches high initial concentrations; however, it is also rapidly eliminated in the Hispaniolan Amazon parrot, and tazobactam has similar pharmacokinetics as piperacillin. Administration of piperacillin at 87 mg/kg IM q3-4h is recommended for this species to control infections attributed to susceptible bacteria with a minimum inhibitory concentration of ≤4 μg/mL
Allopurinol attenuated the chemically-induced hypoxia (hypoxia-reoxygenation) injuries via down-regulation of the transcription factor HIF-1α in neuroblastoma cells
No full textHypoxia and reoxygenation (H/R) conditions cause molecular injuries in neuronal tissues. This study was designed to validate an in vitro model of H/R conditions in Neuro-2A cells and the neuroprotective mechanism(s) of allopurinol on H/R-induced injuries. Hypoxia was induced by using 2-deoxy glucose and Antimycin A and cell viability, intracellular ATP content, reactive oxygen species and nitric oxide concentrations were determined. The expression of hypoxia inducible factor-1 α (HIF-1α) was evaluated by quantitative PCR. Hypoxia resulted in 80% ATP depletion, while more than 80% of the cells remained viable. Co-exposure to H/R and allopurinol protected cells from ATP depletion. Allopurinol treatment significantly (p
Spinosad is a potent inhibitor of canine P-glycoprotein
No full textInhibition of the drug transporter P-glycoprotein (P-gp) by the oral flea preventative spinosad has been suggested as the underlying cause of the drug-drug interaction with ivermectin. In this study, an in vitro model consisting of canine cells was validated to describe the inhibitory effect of drugs on canine P-gp. In this model, ivermectin, cyclosporin, verapamil, loperamide and ketoconazole inhibited P-gp function with IC50 values ranging from 0.1 to 3.7 μmol/L. Spinosad was a potent inhibitor of canine P-gp with an IC50 value of 0.27 μmol/L or 0.2 μg/mL. The risk of spinosad causing P-gp related drug-drug interactions in the dog could be predicted by the IC50 value, the oral dosage and plasma concentrations
Plasma Concentrations of Fentanyl Achieved With Transdermal Application in Chickens
No full textProviding appropriate analgesia is an important concern in any species. Fentanyl, a μ-receptor specific opioid, use is common in mammalian species but has been incompletely evaluated for this purpose in avian species. Transdermal fentanyl patches were applied to domestic chickens (n = 10) of varying breeds for 72 hours. Repeated blood samples were collected from the birds to assess time-concentration of fentanyl and norfentanyl in plasma, as assayed by liquid chromatography-mass spectrometry, throughout patch application and for 48 hours after patch removal. Compartmental modeling was used to characterize the elimination profiles. Evaluation as a large bolus, followed by slower elimination rates over the remaining time, best fit the data as a one-compartment open model. Although maximum plasma fentanyl concentrations varied substantially by individual birds, chickens trended into 2 general groups of maximum plasma concentration, clearance, and volume of distribution, which was attributed to absorption variability. For all birds, harmonic mean of elimination half-life was 7.2 ± 3.7 hours and showed less individual variation than the other pharmacokinetic parameters. Because the application of transdermal fentanyl patches in the chickens achieved plasma fentanyl concentrations considered therapeutic in people, this approach could provide an additional analgesic option for avian patients
Feline hepatic biotransformation and transport mechanisms
No full textHepatic biotransformation and drug transport mechanisms vary significantly between species. While these processes that determine largely the kinetic behavior of drugs have been studied abundantly in dogs, corresponding investigations in cats are hardly available, despite the increasing role of cats in veterinary practice, following the increasing popularity of cats in The Netherlands. Drug intolerance, toxic side effects or a lack of efficacy have been observed when treating feline patients with drugs licensed for other species. In this thesis, we designed a series of experimental in vitro approaches that address the major phases of hepatic drug metabolism and excretion. Main findings: Phase I - Cytochrome P450 (CYP) activities and substrate specificities differ between feline and canine liver microsomes, as expected. Also gender differences are observed. However, fluorometric assays intended for rapid analysis of CYP activity of patient-derived liver biopsies, was found to be non-realistic for a clinical routine as its sensitivity is too low and in turn the amount of liver tissue needed for quantitative results is too high to allow the application in clinical diagnostics. - Diazepam, a drug that is regularly associated with undesirable hepatic side effects in cats, is converted in feline hepatic microsomes mainly into temazepam, while in dog microsomes nordiazepam appears to be the principle metabolite. The lack of quantifiable formation of nordiazepam and oxazepam in feline liver microsomes suggests a feline CYP2B11 ortholog that significantly differs from the corresponding enzyme in dogs. Phase II - A deficient UDP-glucuronosyltransferase (UGT) 1A6 activity was confirmed in feline liver microsomes, and also functional UGT2B homologs are apparently absent in the feline liver. However a functional UGT1A1 and probably other UGT1A homologs in cats were identified, albeit with a lower capacity than dogs. - The overall very low glucuronidation capacity in cats and its small substrate-specificity remain of clinical importance in pharmacotherapy and clinical toxicology. Phase III - Structure and functional characteristics of the feline bile salt export pump (BSEP) was described for the first time and appeared to be very similar between cats, dogs and humans. - BSEP is essential for the transport of bile acids out of the hepatocyte, and inhibition of BSEP, as demonstrated for diazepam and its metabolites, seems to contribute to the observed hepatotoxicity in feline patients after repeated dosing. Everted membrane vesicles transfected with feline BSEP are a valuable screening tool to assess the transport capacity of feline BSEP . - Feline lymphoma cells express the efflux transporter P-glycoprotein (P-gp) at a high rate and hence constitute an easy accessible tool to study P-gp inhibition and drug-drug interactions at the level of P-gp transport. In conclusion, our investigations identified some major differences between hepatic drug metabolism between humans, dogs and cats, explaining various undesirable drug side effects that have been observed in cats and serving as a tool for pre-clinical drug safety assessment
Inhibition of P-glycoprotein by psychotherapeutic drugs in a canine cell model
No full textDrug-drug interactions related to long-term therapies are of increasing concern. Psychotherapeutic drugs, licensed for the use in dogs for the management of separation anxiety and other behavioural disorders, are examples of drugs used in long-term therapies. In an in vitro system with canine P-glycoprotein (P-gp) expressing cell lines, three psychotherapeutic drugs with a different mode of action were tested for their ability to inhibit the canine multidrug transporter P-gp. At 10 μm, the selective serotonin reuptake inhibitor fluoxetine and the tricyclic antidepressant clomipramine inhibited P-gp for 41% and 59%, respectively. In contrast, selegeline did not inhibit the function of the canine P-gp
Galacto-oligosaccharides exert a protective effect against heat stress in a Caco-2 cell model
Get PDFThermal stress can evoke a stress response and enhance the synthesis of heat shock proteins, while gut barrier dysfunction is considered as an important adverse effect of thermal stress. Considering the previously described effects of galacto-oligosaccharides, nowadays mainly used in infant formulas, we hypothesized that galacto-oligosaccharides may protect the intestinal barrier against heat stress. Human epithelial colorectal adenocarcinoma cells were pre-treated with galacto-oligosaccharides prior to thermal stress exposure (40-42 degrees C) for 24 h. Pre-treatment of galacto-oligosaccharides prevented the heat stress-induced upregulation of heat shock proteins and reduced the heat-induced stress response as observed by a decrease in haem oxygenase-1. Galacto-oligosaccharides partly prevented the heat-induced effects on monolayer integrity as measured by transepithelial electrical resistance, paracellular permeability and E-cadherin expression. In addition to their prebiotic effect, galacto-oligosaccharides may have beneficial potency to protect the intestinal epithelial barrier against heat stress and may be an attractive dietary application for people who are at high risk of developing heat stress. (C) 2015 Elsevier Ltd. All rights reserved
Milk Oligosaccharide Variation in Sow Milk and Milk Oligosaccharide Fermentation in Piglet Intestine
Get PDFPorcine milk oligosaccharides (PMOs) were analyzed in six colostrum and two mature milk samples from Dutch Landrace sows. In total, 35 PMOs were recognized of which 13 were new for the PMO literature: Neutral HexNAc-Hex, β4′-galactosyllactose, putative GalNAc(α/β1-3)Gal(β1-4)Glc, lacto-N-fucopentaose-II, lacto-N-tetraose, galactose substituted lacto-N-neohexaose, lacto-N-hexaose and difucosyl-lacto-N-hexaose, and acidic Neu5Ac(α2-6)GlcNAc(β1-3)Gal(β1-4)Glc, sialyllacto-N-tetraose-a and -b, Neu5Ac2-Hex3, and sialyllacto-N-fucopentaose-II. PMOs were analyzed using capillary electrophoresis with laser-induced florescence detection or mass spectrometry and using liquid chromatography with mass spectrometry. Interindividual variation regarding PMO presence and concentration was observed between porcine milks. Within a limited sample set, a 43% decrease of the major PMOs was found during a 1 w lactation period. Interestingly, while some PMOs decreased, some other PMOs increased in concentration. PMOs were also monitored in fecal samples of suckling piglets. In feces of 1-2 d old piglets, few intact PMOs were found, indicating considerable PMO fermentation at early stage of life.</p
Effects of training on equine muscle physiology and muscle adaptations in response to different training approaches
Get PDFIt is well known that exercise induces chemical, metabolic and structural changes in muscles. However, the effect of the type of exercise on these changes has not been thoroughly studied in horses yet, because of a lack of standardized study methods. In this review, the effect of three different types of exercise on muscle adaptation and metabolic responses is investigated. The requirements for power exercise are not the same as for low intensity exercise. Each type of training induces its own shift in muscle fiber typing, as well as in enzyme concentrations and (an) aerobic capacity. These physiological adaptations in response to training facilitate more efficient exercise and therefore increase performance. Hence, it is important to know the adaptations that muscles undergo in response to each type of exercise to optimize training management of sport horses in function of the needs of the discipline in which they compete
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