Showing papers in "Journal of Veterinary Pharmacology and Therapeutics in 2018"
TL;DR: The pharmacological characteristics of five triazines used in veterinary medicine to control protozoal diseases which include coccidiosis, equine protzoal myeloencephalitis, neosporosis, and toxoplasmosis are discussed.
Abstract: Triazines are relatively new antiprotozoal drugs that have successfully controlled coccidiosis and equine protozoal myeloencephalitis. These drugs have favorably treated other protozoal diseases such as neosporosis and toxoplasmosis. In this article, we discuss the pharmacological characteristics of five triazines, toltrazuril, ponazuril, clazuril, diclazuril, and nitromezuril which are used in veterinary medicine to control protozoal diseases which include coccidiosis, equine protozoal myeloencephalitis, neosporosis, and toxoplasmosis.
47 citations
TL;DR: Nonlinear mixed effects (NLME) have been purposely designed to characterize the sources of variability in drug disposition and response and can be used to explore the impact of population-associated variables on the relationship between drug administration, systemic exposure, and the levels of drug residues in tissues.
Abstract: A common feature of human and veterinary pharmacokinetics is the importance of identifying and quantifying the key determinants of between-patient variability in drug disposition and effects. Some of these attributes are already well known to the field of human pharmacology such as bodyweight, age, or sex, while others are more specific to veterinary medicine, such as species, breed, and social behavior. Identification of these attributes has the potential to allow a better and more tailored use of therapeutic drugs both in companion and food-producing animals. Nonlinear mixed effects (NLME) have been purposely designed to characterize the sources of variability in drug disposition and response. The NLME approach can be used to explore the impact of population-associated variables on the relationship between drug administration, systemic exposure, and the levels of drug residues in tissues. The latter, while different from the method used by the US Food and Drug Administration for setting official withdrawal times (WT) can also be beneficial for estimating WT of approved animal drug products when used in an extralabel manner. Finally, NLME can also prove useful to optimize dosing schedules, or to analyze sparse data collected in situations where intensive blood collection is technically challenging, as in small animal species presenting limited blood volume such as poultry and fish.
46 citations
TL;DR: This manuscript is a review of medication classes that have been studied in poultry with an emphasis on drug residue depletion in poultry meat.
Abstract: Poultry meat is widely consumed throughout the world and production practices often include the administration of pharmaceutical products. When appropriate, extra-label drug use of medications is necessary, but scientifically derived drug withdrawal intervals must be observed so that poultry meat is not contaminated with drug residues which could pose health risks to consumers. Over the past decade, there has been increased advocacy for judicious use of antimicrobial drugs for treating food animals. Judicious use of medications is commonly referred to as practices that reduce antibiotic resistance, but also includes residue avoidance. In that light, many investigators have performed scientific studies and have published estimated pharmacokinetic parameters for veterinary medications used in commercial avian species. This manuscript is a review of medication classes that have been studied in poultry (mostly chickens) with an emphasis on drug residue depletion in poultry meat.
31 citations
TL;DR: It is demonstrated that the water temperature had effects on the elimination of both FF and FFA and the formation of FFA, and to treat the infections of bacterial with MIC value ≤ 0.5, more FF or FF at 10 mg/kg BW but with shorter intervals should be intramuscularly given to the infected fish.
Abstract: The pharmacokinetic profiles of florfenicol (FF) or florfenicol amine (FFA) in crucian carp were compared at different water temperatures after single intramuscular administration of FF at 10 mg/kg bodyweight. The concentrations of FF and FFA were determined by a high-performance liquid chromatography method, and then, the concentration versus time data were subjected to compartmental analysis using a one-compartment open model. At the water temperatures of 10, 20, and 25°C, the peak concentrations (Cmax s) of FF were 2.28, 2.29, and 2.34 μg/ml, respectively, while those of FFA were 0.42, 0.71, and 0.82 μg/ml, respectively. And the absorption half-life (t1/2ka ) of FF was 0.21, 0.19, and 0.21 hr, while the elimination half-life (t1/2kel ) was 31.66, 24.77, and 21.48 hr, respectively. For FFA, the formation half-life (t1/2kf ) was 3.85, 8.97, and 12.43 hr, while the t1/2kel was 58.34, 30.27, and 21.22 hr, respectively. The results presented here demonstrated that the water temperature had effects on the elimination of both FF and FFA and the formation of FFA. Based on the T > MIC values calculated here, to treat the infections of bacterial with MIC value ≤ 0.5 μg/ml, FF intramuscularly given at 10 mg/kg bodyweight with a 72-hr interval is sufficient at the water temperature of 10°C, while the intervals of 60 and 48 hr were needed at 20 and 25°C, respectively. But to treat bacterial with higher MIC values, more FF or FF at 10 mg/kg BW but with shorter intervals should be intramuscularly given to the infected fish.
26 citations
TL;DR: The pharmacodynamic data and comparing this with pharmacokinetic data from healthy and infected animals and clinical trial data, it can be seen that the product has a good efficacy against S. suis and A. pleuropneumoniae, in spite of usage over many years, and may be much less efficacious on its own against E. coli.
Abstract: Amoxicillin has become a major antimicrobial substance in pig medicine for the treatment and control of severe, systemic infections such as Streptococcus suis. The minimum inhibitory concentration 90% (MIC 90) is 0.06 μg amoxicillin/ml, and the proposed epidemiological cut-off value (ECOFF) is 0.5 μg/ml, giving only 0.7% of isolates above the ECOFF or of reduced susceptibility. Clinical breakpoints have not been set for amoxicillin against porcine pathogens yet, hence the use of ECOFFs. It has also been successfully used for bacterial respiratory infections caused by Actinobacillus pleuropneumoniae and Pasteurella multocida. The ECOFF for amoxicillin against A. pleuropneumoniae is also 0.5 μg/ml demonstrating only a reduced susceptibility in 11.3% of isolates. Similarly, P. multocida had an ECOFF of 1.0 μg/ml and a reduced susceptibility in only 2.6% of isolates. This reduced susceptibility disappears when combined with the beta-lactamase inhibitor, clavulanic acid, demonstrating that it is primarily associated with beta-lactamase production. In contrast, amoxicillin is active against Escherichia coli and Salmonella species but using ECOFFs of 8.0 and 4.0 μg/ml, respectively, reduced susceptibility can be seen in 70.9% and 67.7% of isolates. These high levels of reduced susceptibility are primarily due to beta-lactamase production also, and most of this resistance can be overcome by the combination of amoxicillin with clavulanic acid. Currently, amoxicillin alone is considered an extremely valuable antimicrobial in both human and animal medicine and remains in the critically important category of antibiotics alongside the fluoroquinolones and macrolides by the World Health Organization as well as the third- and fourth-generation cephalosporins, but these cephalosporins show marked resistance to basic beta-lactamase production and are only destroyed by the extended-spectrum beta-lactamases. Amoxicillin alone and in combination with clavulanic acid are currently classed together in Category 2 in the European Union. By reviewing the pharmacodynamic data and comparing this with pharmacokinetic data from healthy and infected animals and clinical trial data, it can be seen that the product has a good efficacy against S. suis and A. pleuropneumoniae, in spite of usage over many years. However, it may be much less efficacious on its own against E. coli, due to reduced susceptibility and resistance associated with beta-lactamase production, which is largely overcome by the use of clavulanic acid. It is felt that this differentiation may be useful in future classification of amoxicillin alone, in comparison with its combined use with clavulanic acid and thereby preserve the use of the more critically important antibiotics in veterinary medicine and reducing the risk of their resistance being transmitted to human.
25 citations
TL;DR: SEH inhibition with t-TUCB may provide analgesia in horses with inflammatory joint pain, and pain, lameness, and tactile allodynia were significantly lower with 1 mg/kg t- TUCB, but not the other doses.
Abstract: This study determined the pharmacokinetics, antinociceptive, and anti-inflammatory effects of the soluble epoxide hydrolase (sEH) inhibitor t-TUCB (trans-4-{4-[3-(4-Trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid) in horses with lipopolysaccharide (LPS)-induced radiocarpal synovitis. A total of seven adult healthy mares (n=4-6/treatment) were administered 3g LPS into one radiocarpal joint and t-TUCB intravenously (i.v.) at 0 (control), 0.03, 0.1, 0.3, and 1mg/kg in a blinded, randomized, crossover design with at least 3weeks washout between. Two investigators independently assigned pain scores (at rest, walk and trot) and lameness scores before and up to 48hr after t-TUCB/LPS. Responses to touching the joint skin to assess tactile allodynia, plasma, and synovial fluid (SF) t-TUCB concentrations were determined before and up to 48hr after t-TUCB/LPS. Blood and SF were collected for clinical laboratory evaluations before and up to 48hr after t-TUCB/LPS. Areas under the curves of pain and lameness scores were calculated and compared between control and treatments. Data were analyzed using repeated measures ANOVA with Dunnett or Bonferroni post-test. p<.05 was considered significant. Data are mean +/- SEM. Compared to control, pain, lameness, and tactile allodynia were significantly lower with 1mg/kg t-TUCB, but not the other doses. For 0.1, 0.3, and 1mg/kg t-TUCB treatments, plasma terminal half-lives were 13 +/- 3, 13 +/- 0.5, and 24 +/- 5hr, and clearances were 68 +/- 15, 48 +/- 5, and 14 +/- 1 mlhr(-1)kg(-1). The 1 mg/kg t-TUCB reached the SF at high concentrations. There were no important anti-inflammatory effects. In conclusion, sEH inhibition with t-TUCB may provide analgesia in horses with inflammatory joint pain.
22 citations
TL;DR: Studies testing the efficacy of praziquantel for treatment of platyhelminthes are reviewed along with an assessment of routes of administration, pharmacokinetics, and toxicity information.
Abstract: Fish are common definitive and intermediate hosts for a variety of parasitic flatworms. In unstressed wild populations, parasitic infections often go unnoticed and are perceived to represent a lesser threat to fish health. In contrast, platyhelminth parasitism of captive fish often results in decreased weight gain and increased mortality which often necessitates chemotherapeutic treatment. The presence of platyhelminth parasites in fish tissues is not only unappealing but in some cases also represents a threat to human health. In veterinary medicine, one of the most commonly used agents with anti-flatworm activity is praziquantel; yet, no praziquantel products are labeled for use in fish in the United States. Veterinarians may use praziquantel preparations approved for other vertebrate species under the Animal Medicinal Drug Use Clarification Act (AMDUCA). However, such extra-label use should be informed by scientific evidence including efficacy and tissue residue studies. Herein, we review studies testing the efficacy of praziquantel for treatment of platyhelminthes along with an assessment of routes of administration, pharmacokinetics, and toxicity information.
22 citations
TL;DR: The results of the first field trial on diseased honeybee colonies with BPC 157 indicate significant therapeutic effects with the used oral therapy with B PC 157 supplementation, and the number of N. ceranae spores per honeybee gradually decreased as well.
Abstract: Nosema ceranae can cause major problems, such as immune suppression, gut epithelial cell degeneration, reduced honeybee lifespan, or suddenly colony collapse. As a novel approach in therapy, we hypothesize the stable gastric pentadecapeptide BPC 157 in honeybee therapy, to control N. ceranae invasions in apiary conditions: BPC 157 treated sugar syrup (0.25 L sugar syrup supplemented with 0.1 μg/ml BPC 157), as well as the pure sugar syrup (0.25 L sugar syrup; control), was administered to honeybee colonies in feeders situated under the roof of the hives, during 21 consecutive days, at the end of beekeeping season. The strength of honeybee colonies was increased 20 and 30 days after initial feeding with BPC 157 supplement (Day 1, 36.100 ± 698; Day 20, 64.860 ± 468; Day 30, 53.214 ± 312 estimated number of honeybees), in field conditions. The similar successful outcome occurs with the N. ceranae spore loads counted in the homogenates of sampled adult honeybees (Day 1, 6.286 ± 2.336; Day 20, 3.753 ± 1.835; Day 30, 2.005 ± 1.534 million spores/bee). Accordingly, with the noted increased strength of the colonies fed with sugar syrup supplemented with BPC 157, the number of N. ceranae spores per honeybee gradually decreased as well. Besides, honeybees infected with N. ceranae fed with sugar syrup exhibited severe damage of midgut wall layers and epithelial cells. By contrast, in honeybees infected with N. ceranae fed with sugar syrup supplemented with BPC 157, all damages were markedly attenuated, damages of the outer muscular coat, in particular. In conclusion, the results of the first field trial on diseased honeybee colonies with BPC 157 indicate significant therapeutic effects with the used oral therapy with BPC 157 supplementation.
22 citations
TL;DR: The results of this study suggest that NAC represents a potential additional treatment option that could be considered to improve the health condition and minimize the duration of hospitalization in case of canine parvoviral diarrhea.
Abstract: Previously, antioxidants have not been evaluated for treatment of parvoviral diarrhea in dogs. In this study, antioxidant potential of N-acetylcysteine (NAC) in dogs infected with canine parvovirus with a nonblinded randomized clinical trial has been carried out. A total 18 parvo-infected dogs were randomly divided into two groups: nine parvo-infected dogs were treated with supportive treatment and nine parvo-infected dogs were treated with NAC along with supportive treatment. Simultaneously, nine healthy dogs were kept as healthy control. In parvo-infected dogs, marked hemoconcentration, leucopenia, neutropenia and oxidative stress were noticed compared to healthy dogs. The NAC treatment progressively improved the leukocyte, neutrophil, monocyte, and eosinophil counts over the time in parvovirus-infected dogs compared to dogs that received only supportive treatment. In addition, NAC treatment significantly improved glutathione S-transferase (GST) activity and decreased nitrite plus nitrate (NOx) and malondialdehyde (MDA) concentrations on day 3 and 5 compared to supportive treatment in parvo-infected dogs. However, supportive treatment alone failed to ameliorate oxidative stress in the infected dogs till day 5. The results of this study suggest that NAC represents a potential additional treatment option that could be considered to improve the health condition and minimize the duration of hospitalization in case of canine parvoviral diarrhea.
21 citations
TL;DR: Sources of population variability associated with drug metabolism and membrane transport are considered and the use of modeling and simulation is highlighted to support an appreciation of the variability in dose-exposure-response relationships.
Abstract: There is an increasing effort to understand the many sources of population variability that can influence drug absorption, metabolism, disposition, and clearance in veterinary species. This growing interest reflects the recognition that this diversity can influence dose-exposure-response relationships and can affect the drug residues present in the edible tissues of food-producing animals. To appreciate the pharmacokinetic diversity that may exist across a population of potential drug product recipients, both endogenous and exogenous variables need to be considered. The American Academy of Veterinary Pharmacology and Therapeutics hosted a 1-day session during the 2017 Biennial meeting to explore the sources of population variability recognized to impact veterinary medicine. The following review highlights the information shared during that session. In Part I of this workshop report, we consider sources of population variability associated with drug metabolism and membrane transport. Part II of this report highlights the use of modeling and simulation to support an appreciation of the variability in dose-exposure-response relationships.
19 citations
TL;DR: Findings indicate that despite induction of glandular disease grade ≥2, phenylbutazone did not decrease basal glandular gastric prostaglandin E2 concentration.
Abstract: In equids, phenylbutazone at high doses induces gastric disease, primarily in the glandular portion of the stomach. However, the mechanism of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric disease in horses has yet to be determined. While phenylbutazone-associated ulceration is often attributed to a decrease in basal gastric prostaglandins, this has not been demonstrated in the horse. Twelve horses were randomly assigned to treatment (n = 6; 4.4 mg/kg phenylbutazone PO in 20 ml molasses q 12 hr for 7 days) or placebo (n = 6; 20 ml molasses PO q 12 hr for 7 days) groups. Before treatment and 3 and 7 days after initiation of treatment, gastroscopy was performed and glandular gastric biopsies were collected and frozen at -80°C. Glandular disease was assessed on a scale of 0-4. Prostaglandin E2 concentrations in biopsies were measured using a commercially available enzyme-linked immunosorbent assay. All phenylbutazone-treated horses developed grade ≥2 glandular disease. Prostaglandin concentrations increased over time (p = .0017), but there was no effect of treatment (p = .49). These findings indicate that despite induction of glandular disease grade ≥2, phenylbutazone did not decrease basal glandular gastric prostaglandin E2 concentration.
TL;DR: It is possible and practical to obtain therapeutic blood concentrations of enrofloxacin in the crucian carp using IM, PO and bath immersion administration and the area under the concentration-time curve (AUC) values were 223.46, 162.72 and 14.91 μg hr/ml.
Abstract: The pharmacokinetics of enrofloxacin (ENR) was studied in crucian carp (Carassius auratus gibelio) after single administration by intramuscular (IM) injection and oral gavage (PO) at a dose of 10 mg/kg body weight and by 5 mg/L bath for 5 hr at 25°C. The plasma concentrations of ENR and ciprofloxacin (CIP) were determined by HPLC. Pharmacokinetic parameters were calculated based on mean ENR or CIP concentrations using WinNonlin 6.1 software. After IM, PO and bath administration, the maximum plasma concentration (Cmax) of 2.29, 3.24 and 0.36 μg/ml was obtained at 4.08, 0.68 and 0 hr, respectively; the elimination half-life (T1/2β) was 80.95, 62.17 and 61.15 hr, respectively; the area under the concentration–time curve (AUC) values were 223.46, 162.72 and 14.91 μg hr/ml, respectively. CIP, an active metabolite of enrofloxacin, was detected and measured after all methods of drug administration except bath. It is possible and practical to obtain therapeutic blood concentrations of enrofloxacin in the crucian carp using IM, PO and bath immersion administration.
TL;DR: An aspirin dosage of 2 mg/kg q24h consistently inhibits platelet function without decreasing prostacyclin synthesis significantly more than lower aspirin dosages.
Abstract: Established "low" aspirin dosages inconsistently inhibit platelet function in dogs. Higher aspirin dosages consistently inhibit platelet function, but are associated with adverse effects. The objectives of this study were to use an escalation in dosage to determine the lowest aspirin dosage that consistently inhibited platelet function without inhibiting prostacyclin synthesis. Eight dogs were treated with five aspirin dosages: 0.5 mg/kg q24h, 1 mg/kg q24h, 2 mg/kg q24h, 4 mg/kg q24h and 10 mg/kg q12h for 7 days. Utilizing aggregometry and a whole-blood platelet function analyzer (PFA-100), platelet function was evaluated before and after treatment. Urine 11-dehydro-thromboxane-B2 (11-dTXB2 ) and 6-keto-prostaglandin-F1α (6-keto-PGF1α ), were measured. Compared to pretreatment, there were significant post-treatment decreases in the maximum aggregometry amplitude and increases in the PFA-100 closure times for all dosages expect 0.5 mg/kg q24h. There was no difference in amplitude or closure time among the 2 mg/kg q24h, 4 mg/kg q24h, and 10 mg/kg q12h dosages. Compared to pretreatment values, there was a significant decrease in urinary 11-dTXB2 -to-creatinine and 6-keto-PGF1α -to-creatinine ratios, but there was no dose-dependent decrease for either metabolite. An aspirin dosage of 2 mg/kg q24h consistently inhibits platelet function without decreasing prostacyclin synthesis significantly more than lower aspirin dosages.
TL;DR: There were no clinically relevant differences in clinical pathology test results between the capromorelin and placebo groups in either study and normal clinical observations were limited to emesis, hypersalivation, lethargy/depression, head shaking and lip smacking.
Abstract: Capromorelin is a ghrelin receptor agonist that is FDA approved for appetite stimulation in dogs. The objective of this study was to evaluate the safety of daily oral administration of capromorelin to cats over a range of doses and for an extended period. Two randomized, controlled studies were conducted: in Study 1, cats (n = 6 per group) received placebo or capromorelin at a dose of 9, 15, 30 or 60 mg/kg once daily for 14 days; and in Study 2, cats received capromorelin at 6 mg/kg (n = 8) or placebo (n = 4) once daily for 91 days. Cats were evaluated using clinical observations and clinical pathology test results for both studies, with the addition of postmortem examination in Study 1 and measurements of growth hormone and insulin-like growth factor 1 in Study 2. Abnormal clinical observations were limited to emesis, hypersalivation, lethargy/depression, head shaking and lip smacking, which occurred more frequently in the capromorelin-treated groups than in the placebo group. There were no clinically relevant differences in clinical pathology test results between the capromorelin and placebo groups in either study.
TL;DR: The accumulation of the cartilage and up-regulated Hsp90 are associated with TD pathogenesis and irregular chondrocyte morphology in TD is along with reduced aggrecan levels in the growth plate.
Abstract: Tibial dyschondroplasia (TD) is a bone defect of broilers and other poultry birds that disturbs growth plate and it causes lameness. Previously we evaluated differential expression of multiple genes involved in growth plate angiogenesis and reported the safety and efficacious of medicinal plant root extracted for controlling TD. In this study, clinical and protective effect of an antibiotic Novobiocin (Hsp90 inhibitor) and expression of Hsp90 and proteoglycan aggrecan was examined. The chicks were divided into three groups; Control, thiram-induced TD, and Novobiocin injected TD. After the induction of TD, the Novobiocin was administered through intraperitoneal route to TD-affected birds until the end of the experiment. The expressions and localization of Hsp90 were evaluated by qRT-PCR, immunohistochemistry (IHC) and western blot, respectively. Morphological, histological examinations, and serum biomarker levels were evaluated to assess specificity and protective effects of Novobiocin. The results showed that TD causing retarded growth, enlarged growth plate, distended chondrocytes, irregular columns of cells, decreased antioxidant capacity, reduced protein levels of proteoglycan aggrecan, and upregulated in Hsp90 expression (p < 0.05) in dyschondroplastic birds as compared with control. Novobiocin treatment restored growth plate morphology, reducing width, stimulated chondrocyte differentiation, sprouting blood vessels, corrected oxidative imbalance, decreased Hsp90 expressions and increased aggrecan level. Novobiocin treatment controlled lameness and improved growth in broiler chicken induced by thiram. In conclusion, the accumulation of the cartilage and up-regulated Hsp90 are associated with TD pathogenesis and irregular chondrocyte morphology in TD is along with reduced aggrecan levels in the growth plate. Our results indicate that Novobiocin treatment has potential to reduce TD by controlling the expression of Hsp90 in addition to improve growth and hepatic toxicity in broiler chicken.
TL;DR: Findings in conjunction with MIC90 data suggested that ENR at the dose of 7.81 mg/kg predicted a positive clinical outcome and minimize the risk of emergence of resistance.
Abstract: The pharmacokinetic (PK) properties of enrofloxacin (ENR) and its metabolite ciprofloxacin (CIP) were investigated in crucian carp following oral administration at different dose levels (5, 10, 20, 40 mg/kg body weight). The disposition kinetics of ENR was found to be linear over the dose range studied. Serum half-lives ranged from 64.56 to 72.68 hr. The in vitro and ex vivo activities of ENR in serum against a pathogenic strain of Aeromonas hydrophila were determined. In vitro and ex vivo bactericidal activity of ENR was concentration dependent. Dosing of 10 mg/kg resulted in an AUC/minimum inhibitory concentration (MIC) ratio of 368.92 hr and a Cmax /MIC ratio of 7.23, respectively, against A. hydrophila 147 (MIC = 0.48 μg/ml), indicating a likely high level of effectiveness in clinical infections caused by A. hydrophila with MIC value ≤ 0.48 μg/ml. Modeling of ex vivo growth inhibition data to the sigmoid Emax equation provided the values of AUC24 hr /MIC required to produce bacteriostasis, bactericidal activity, and elimination of bacteria, these values were 21.70, 53.01, and 125.21 hr, respectively. These findings in conjunction with MIC90 data suggested that ENR at the dose of 7.81 mg/kg predicted a positive clinical outcome and minimize the risk of emergence of resistance.
TL;DR: Tolfenamic acid indicated a long half-life and high bioavailability following IM, SC, and OR administrations at 2 mg/kg and may be used in different routes and doses in sheep; however, further studies are needed to determine the clinical efficacy of TA during the inflammatory and painful conditions and the pharmacokinetics and safety of repeated administration in sheep.
Abstract: The pharmacokinetics, bioavailability, and tolerability of tolfenamic acid (TA) were determined after treating sheep with TA via different routes and doses. This crossover study was carried out with a washout period of 15 days. In the study, 16 clinically healthy sheep were randomly assigned to two equal groups. In the first group (n = 8), animals received TA by intravenous (IV), intramuscular (IM), subcutaneous (SC), or oral (OR) routes at 2 mg/kg. In the second group (n = 8), TA was administered intravenously to each sheep at 2, 4, 8, and 16 mg/kg. Plasma samples were analyzed with a high-performance liquid chromatography assay. Noncompartmental pharmacokinetic analyses were used to evaluate the data. The area under the concentration-time curves (AUC0-∞ ), elimination half-life (t1/2ʎz ), and the mean residence time (MRT) significantly differed among the administration routes at 2 mg/kg of TA. Following IM, SC, and OR administrations, TA demonstrated different peak concentrations (Cmax ) and time to reach Cmax (Tmax ), with a bioavailability of 163%, 127%, and 107%, respectively. The dose-normalized AUC0-∞ revealed a significant difference among the dose groups; however, the relationship between dose and AUC0-∞ was linear. Both t1/2ʎz and MRT increased depending on the dose. Although the total clearance (ClT ) decreased depending on dose, the volume of distribution at steady-state (Vss ) increased. Tolfenamic acid indicated a long half-life and high bioavailability following IM, SC, and OR administrations at 2 mg/kg. TA exhibited linear kinetics and was well tolerated by the animals, except at 16 mg/kg. Thus, TA may be used in different routes and doses (≤8 mg/kg) in sheep; however, further studies are needed to determine the clinical efficacy of TA during the inflammatory and painful conditions and the pharmacokinetics and safety of repeated administration in sheep.
TL;DR: The S-isomer is the predominant isomer in loggerhead sea turtles, similar to most mammals, despite administration of a 50:50 racemic mixture, and a dose of 2 mg/kg either IM or IV every 24 hr is likely appropriate for loggerhead turtles.
Abstract: Ketoprofen is a nonsteroidal anti-inflammatory and analgesic agent that nonselectively inhibits cyclooxygenase, with both COX-1 and COX-2 inhibition. Recent studies on COX receptor expression in reptiles suggest that nonselective COX inhibitors may be more appropriate than more selective inhibitors in some reptiles, but few pharmacokinetic studies are available. The goal of this study was to determine single- and multidose (three consecutive days) pharmacokinetics of racemic ketoprofen administered intravenously and intramuscularly at 2 mg/kg in healthy juvenile loggerhead turtles (Caretta caretta). The S-isomer is the predominant isomer in loggerhead sea turtles, similar to most mammals, despite administration of a 50:50 racemic mixture. Multidose ketoprofen administration demonstrated no bioaccumulation; therefore, once-daily dosing will not require dose adjustment over time. S-isomer pharmacokinetic parameters determined in this study were Cmax of 10.1 μg/ml by IM injection, C0 of 13.4 μg/ml by IV injection, AUC of 44.7 or 69.4 μg*hr/ml by IM or IV injection, respectively, and T½ of 2.8 or 3.6 hr by IM or IV injection, respectively. Total ketoprofen plasma concentrations were maintained for at least 12 hr above concentrations determined to be effective for rats and humans. A dose of 2 mg/kg either IM or IV every 24 hr is likely appropriate for loggerhead turtles.
TL;DR: Although further studies are needed, rectal administration seems to be the least suitable route of administration for MT in the dog, and the concentrations of MAA and AA were approximately double those in the PO groups.
Abstract: Metamizole (MT), an analgesic and antipyretic drug, is rapidly hydrolyzed to the active primary metabolite 4-methylaminoantipyrine (MAA) and relatively active secondary metabolite 4-aminoantipyrine (AA). The aim of this study was to assess the pharmacokinetic profiles of MAA and AA after dose of 25 mg/kg MT by intravenous (i.v.), intramuscular (i.m.), oral (p.o.), and rectal (RC) routes in dogs. Six dogs were randomly allocated to an open, single-dose, four-treatment, four-phase, unpaired, crossover study design. Blood was collected at predetermined times within 24 hr, and plasma was analyzed by a validated HPLC-UV method. Plasma concentrations of MAA and AA after i.v., i.m., p.o., and RC administrations of MT were detectable from 5 (i.v. and i.m.) or 30 (p.o. and RC) min to 24 hr in all dogs. The highest concentrations of MAA were found in the i.v., then i.m., p.o., and RC groups. Plasma concentrations of AA were similar for i.v., i.m., and RC, and the concentrations were approximately double those in the PO groups. The AUCEV/IV ratio for MAA was 0.75 ± 0.11, 0.59 ± 0.08, and 0.32 ± 0.05, for i.m., p.o., and RC, respectively. The AUCEV/IV ratio for AA was 1.21 ± 0.33, 2.17 ± 0.62, and 1.08 ± 0.19, for i.m., p.o., and RC, respectively. Although further studies are needed, rectal administration seems to be the least suitable route of administration for MT in the dog.
TL;DR: Based on in vitro characterization, all four ionophores offer potentially novel treatments against bovine mastitis but in vivo studies will be essential to determine whether acceptable safety and efficacy is present following intramammary administration.
Abstract: Increasing reports of multidrug-resistant bacterial infections in animals has created a need for novel antimicrobial agents that do not promote cross-resistance to critically important antimicrobial classes used in human medicine. In response to the recent emergence of antimicrobial resistance in several bovine mastitis pathogens, in vitro antimicrobial susceptibility was determined for four polyether ionophores (lasalocid, monensin, narasin and salinomycin) against Staphylococcus spp. and Streptococcus spp. isolated from clinical cases. In addition, erythrocyte haemolysis and WST-1 cell proliferation assays were used to assess in vitro mammalian cell cytotoxicity and biofilm susceptibility testing was performed using the minimum biofilm eradication concentration (MBEC™) biofilm assay. Lasalocid, monensin, narasin and salinomycin exhibited bacteriostatic antimicrobial activity against all pathogens tested, including methicillin-resistant staphylococci, with MIC90 values <16 μg/ml. Narasin and monensin displayed the least toxicity against mammalian cell lines and all compounds significantly reduced viable cell numbers in a Staphylococcus aureus biofilm. Based on in vitro characterization, all four ionophores offer potentially novel treatments against bovine mastitis but in vivo studies will be essential to determine whether acceptable safety and efficacy is present following intramammary administration.
TL;DR: Pharmacokinetic parameters should be interpreted with respect to LLOQ, as lower limits can influence estimated parameters, such as elimination half-life or systemic clearance and have significant impact on dosage regimen selection in clinical practice.
Abstract: This study describes the pharmacokinetics of intravenously administered (i.v.) fentanyl citrate, and its primary metabolite norfentanyl in Holstein calves. Eight calves (58.6 ± 2.2 kg), aged 3-4 weeks, were administered fentanyl citrate at a single dose of 5.0 μg/kg i.v. Blood samples were collected from 0 to 24 hr. Plasma (nor)fentanyl concentrations were determined using liquid chromatography with mass spectrometry and a lower limit of quantification (LLOQ) of 0.03 ng/ml. To explore the effect of analytical performance on fentanyl parameter estimation, the noncompartmental pharmacokinetic analysis was then repeated with a hypothetical LLOQ value of 0.05 ng/ml. Terminal elimination half-life was estimated at 12.7 and 3.6 hr for fentanyl and norfentanyl, respectively. For fentanyl, systemic clearance was estimated at 2.0 L hr-1 kg-1 , volume of distribution at steady-state was 24.8 L/kg and extraction ratio was 0.42. At a hypothetical LLOQ of 0.05 ng/ml fentanyl half-life, volume of distribution at steady-state and clearance were, respectively, of 3.0 hr, 8.8 L/kg and 3.4 L kg-1 hr-1 . Fentanyl citrate administered i.v. at 5.0 μg/kg can reach levels associated with analgesia in other species. Pharmacokinetic parameters should be interpreted with respect to LLOQ, as lower limits can influence estimated parameters, such as elimination half-life or systemic clearance and have significant impact on dosage regimen selection in clinical practice.
TL;DR: A clearer picture is provided of the role of individual CYPs in the complex metabolism of tramadol in dogs using recombinant enzymes, untreated dog liver microsomes, inhibitor-treated DLMs, and DLMs from CYP inducer-treated dogs to evaluate whether (+)-tramadol, (+)-M1, (+-M2, or (-)-M5 are substrates of canine P-glycoprotein, thereby limiting their distribution into the central nervous system.
Abstract: We previously showed that (+)-tramadol is metabolized in dog liver to (+)-M1 exclusively by CYP2D15 and to (+)-M2 by multiple CYPs, but primarily CYP2B11. However, (+)-M1 and (+)-M2 are further metabolized in dogs to (+)-M5, which is the major metabolite found in dog plasma and urine. In this study, we identified canine CYPs involved in metabolizing (+)-M1 and (+)-M2 using recombinant enzymes, untreated dog liver microsomes (DLMs), inhibitor-treated DLMs, and DLMs from CYP inducer-treated dogs. A canine P-glycoprotein expressing cell line was also used to evaluate whether (+)-tramadol, (+)-M1, (+)-M2, or (+)-M5 are substrates of canine P-glycoprotein, thereby limiting their distribution into the central nervous system. (+)-M5 was largely formed from (+)-M1 by recombinant CYP2C21 with minor contributions from CYP2C41 and CYP2B11. (+)-M5 formation in DLMs from (+)-M1 was potently inhibited by sulfaphenazole (CYP2C inhibitor) and chloramphenicol (CYP2B11 inhibitor) and was greatly increased in DLMs from phenobarbital-treated dogs. (+)-M5 was formed from (+)-M2 predominantly by CYP2D15. (+)-M5 formation from (+)-M1 in DLMs was potently inhibited by quinidine (CYP2D inhibitor) but had only a minor impact from all CYP inducers tested. Intrinsic clearance estimates showed over 50 times higher values for (+)-M5 formation from (+)-M2 compared with (+)-M1 in DLMs. This was largely attributed to the higher enzyme affinity (lower Km) for (+)-M2 compared with (+)-M1 as substrate. (+)-tramadol, (+)-M1, (+)-M2, or (+)-M5 were not p-glycoprotein substrates. This study provides a clearer picture of the role of individual CYPs in the complex metabolism of tramadol in dogs.
TL;DR: The results showed that lipid peroxidation of pig liver tissue occurred with all EF doses, androteomic analysis revealed increased protein expression of carboxylesterase and alpha-enolase in microsomes as a stress response to EF.
Abstract: Enrofloxacin (EF) is a widely used fluoroquinolone, usually regarded as a safe and effective treatment for bacterial infections. Adverse effects of EF have previously been demonstrated in some species, but so far there have been no studies looking specifically at the impact of EF on pigs. In this study, three different doses of EF (5, 25 and 125 mg kg bw-1 ) were administrated to Bama pigs. The results showed that lipid peroxidation of pig liver tissue occurred with all EF doses. The 125 mg kg dose of EF induced catalase (CAT) and glutathione peroxidase (GSH-px) and increased CYP450 content in pig liver microsomes. The activity of microsomal NADPH-cytochrome C reductase (NCCR) was elevated at both the 25 and 125 mg kg doses of EF. Microsomal erythromycin N-demethylase (ERND) and aminopyrin N-demethylase (AND) were inhibited by high doses of EF, while aniline-4-hydroxylase (AH) was unaffected. None of the EF treatments affected superoxide dismutase (SOD) or cytochrome b5 content. Antioxidases and microsomal enzymes may work together to resist the adverse effects of EF. Proteomic analysis revealed increased protein expression of carboxylesterase (CES) and alpha-enolase (ENO1) in microsomes as a stress response to EF. These results provide new information about the adverse effect of fluoroquinolones and help guide their usage more effectively in the clinic or animal breeding.
TL;DR: Single and repeat topical doses of a novel mirtazapine transdermal ointment achieve measurable plasma concentrations in cats.
Abstract: Single and multiple dose pharmacokinetics (PK) of mirtazapine transdermal ointment applied to the inner ear pinna of cats were assessed Study 1 was a randomized, cross-over single dose study (n = 8) Cats were treated once with 05 mg/kg of mirtazapine transdermal ointment applied topically to the inner ear pinna (treatment) or administered orally (control) and then crossed over after washout Plasma was collected predose and at specified intervals over 96 hr following dosing Study 2 was a multiple dose study (n = 8) Cats were treated daily for 14 days with 05 mg/kg of mirtazapine transdermal ointment applied topically to the inner pinna Plasma was collected on Day 13 predose and at specified intervals over 96 hr following the final dose In Study 1, single transdermal administration of mirtazapine resulted in mean Tmax = 159 hr, Cmax = 215 ng/mL, AUC0-24 = 100 ng*hr/mL, AUC0-∞ = 260 ng*hr/mL and calculated half-life = 268 hr Single oral administration of mirtazapine resulted in mean Tmax = 11 hr, Cmax = 831 ng/mL, AUC0-24 = 377 ng*hr/mL, AUC0-∞ = 434 ng*hr/mL and calculated half-life = 101 hr Mean relative bioavailability (F) of transdermal to oral dosing was 649% In Study 2, daily application of mirtazapine for 14 days resulted in mean Tmax = 21 hr, Cmax = 396 ng/mL, AUC0-24 = 400 ng*hr/mL, AUC0-∞ = 647 ng*hr/mL and calculated half-life = 207 hr Single and repeat topical doses of a novel mirtazapine transdermal ointment achieve measurable plasma concentrations in cats
TL;DR: The detailed pharmacokinetic profiles of free and total CEF showed that this drug is widely distributed and rapidly eliminated and may contribute to a better understanding of the usage of ceftiofur hydrochloride injection in Holstein dairy cows.
Abstract: Ceftiofur (CEF), a broad-spectrum third-generation cephalosporin, exhibits a good activity against a broad range of gram-negative and gram-positive bacteria, including many that produce β-lactamase. To design a rational dosage regimen for the drug in lactating Holstein dairy cows, the pharmacokinetic properties of ceftiofur hydrochloride injection were investigated in six cows after intravenous, intramuscular, and subcutaneous administration of single dose of 2.2 mg/kg BW (body weight). Plasma concentration-time curves and relevant parameters were best described by noncompartmental analysis through WinNonlin 6.3 software. After subcutaneous administration, the absolute bioavailability was 61.12% and the T1/2λz (elimination half-life) was 8.67 ± 0.72 hr. The Cmax (maximum plasma concentration) was 0.88 ± 0.21 μg/ml and Tmax (the time after initial injection to when Cmax occurs) was 1.50 ± 0.55 hr. The MRT (mean residence time) was 11.00 ± 0.30 hr. Following intramuscular administration, the Cmax (1.09 ± 0.21 μg/ml) was achieved at Tmax (1.20 ± 0.26 hr) with an absolute availability of 70.52%. In this study, the detailed pharmacokinetic profiles of free and total CEF showed that this drug is widely distributed and rapidly eliminated and may contribute to a better understanding of the usage of ceftiofur hydrochloride injection in Holstein dairy cows.
TL;DR: The present results suggest that MET is converted into the active metabolites in cats as in humans, and further pharmacodynamics and safety studies should be performed before any clinical use.
Abstract: This study was performed to determine pharmacokinetic profiles of the two active metabolites of the analgesic drug metamizole (dipyrone, MET), 4-methylaminoantipyrine (MAA), and 4-aminoantipyrine (AA), after intravenous (i.v., intramuscular (i.m.), and oral (p.o.) administration in cats. Six healthy mixed-breed cats were administered MET (25 mg/kg) by i.v., i.m., or p.o. routes in a crossover design. Adverse clinical signs, namely salivation and vomiting, were detected in all groups (i.v. 67%, i.m. 34%, and p.o. 15%). The mean maximal plasma concentration of MAA for i.v., i.m., and p.o. administrations was 148.63 ± 106.64, 18.74 ± 4.97, and 20.59 ± 15.29 μg/ml, respectively, with about 7 hr of half-life in all routes. Among the administration routes, the area under the plasma concentration curve (AUC) value was the lowest after i.m. administration and the AUCEV/i.v . ratio was higher in p.o. than the i.m. administration without statistical significance. The plasma concentration of AA was detectable up to 24 hr, and the mean plasma concentrations were smaller than MAA. The present results suggest that MET is converted into the active metabolites in cats as in humans. Further pharmacodynamics and safety studies should be performed before any clinical use.
TL;DR: Danofloxacin, at a dose of 5 mg/kg b.w., seems to be insufficient for ducks infected with P. multocida at the clinical recommended dose, which is far from the PK/PD target (125 hr) of fluoroquinolones.
Abstract: Pasteurella multocida (P. multocida) infection causes substantial economic loss in the duck industry. Danofloxacin, a fluoroquinolone solely used in animals, shows good antibacterial activity against P. multocida. In this study, the in vitro pharmacodynamics of danofloxacin against P. multocida was studied. The serum and lung tissue pharmacokinetics of danofloxacin were studied in healthy and P. multocida infected ducks following oral administration of a single dose of 5 mg/kg body weight (b.w.). The MIC, MBC and MPC of danofloxacin against P. multocida (C48-1 ) were 0.25, 1 and 3.2 μg/ml, respectively. The Cmax was 0.34 μg/ml, attained at 2.03 hr in healthy ducks, and was 0.35 μg/ml, attained at 2.87 hr in diseased ducks. Compared to the serum pharmacokinetics of danofloxacin in healthy ducks, the absorption rate and extent were similar in healthy and diseased animals. In contrast, the elimination rate was slower, with an elimination half-life (T1/2β ) of 13.17 and 16.18 hr for healthy and infected animals, respectively; the AUCs in the two groups were 5.70 and 7.68 μg hr/ml, respectively, which means the total amount of drug in the circulation was increased in the infected ducks. The maximum concentration in lung tissues between healthy and infected animals was not significantly different (8.96 vs. 8.93 μg/g). However, the Tmax in healthy ducks was longer than that in infected ducks (4 hr vs. 1.75 hr), which means that the distribution rate of danofloxacin was slower in healthy ducks. The concentration of danofloxacin in lung tissues was approximately 24-fold higher than that in the serum. In the serum pharmacokinetic profiles, the ƒAUC0-24 hr /MIC was 18.19 in healthy ducks and was 25.04 in P. multocida infected ducks at the clinical recommended dose, which is far from the PK/PD target (125 hr) of fluoroquinolones. Danofloxacin, at a dose of 5 mg/kg b.w., seems to be insufficient for ducks infected with P. multocida, with an MIC equal to 0.25 μg/ml.
TL;DR: The findings indicated that sole treatment with Masti Veyxym® in nonsevere CM cases may constitute an alternative therapy to reduce antibiotics and noninferiority compared to the reference treatment was proven.
Abstract: A nonblinded, positively controlled, noninferiority trial was conducted to evaluate the efficacy of an alternative, nonantibiotic therapy with Masti Veyxym® to reduce ineffective antibiotic usage in the treatment of nonsevere clinical mastitis (CM) in cows with longer lasting udder diseases. The solely intramammary treatment with Masti Veyxym® (three applications, 12 hr apart) and the combined treatment with Masti Veyxym® and antibiotics as usual on the farm according to label of the respective product were compared with the reference treatment of solely antibiotic therapy. The matched field study was conducted on eight free-stall dairy farms located in Eastern Germany. Cases of mild-to-moderate CM in cows with longer lasting high somatic cell counts in preceding dairy herd improvement test days and with previous CM cases in current lactation were randomly allocated to one of the three treatment groups. A foremilk sample of the affected quarter was taken before treatment and again approximately 14 days and 21 days after the end of therapy for cyto-bacteriological examination. Primary outcomes were clinical cure (CC) and no CM recurrence within 60 days after the end of treatment (no R60). Bacteriological cure (BC) and quarter somatic cell count (QSCC) cure were chosen as secondary outcomes although low probabilities of BC and QSCC cure for selected cows were expected. The study resulted in the following findings: the pathogens mostly cultured from pretreatment samples were Streptococcus uberis, followed by Staphylococcus aureus and coagulase-negative staphylococci. There were no significant differences between the two test treatments in comparison with the reference treatment regarding all outcome variables. The sole therapy with Masti Veyxym® resulted in a numerically lower likelihood of BC without significant differences to the reference treatment. The combined therapy group showed a numerically higher nonrecurrence rate than the two other treatment groups and noninferiority compared to the reference treatment was proven. Having regard to the selection criteria of cows in this study, the findings indicated that sole treatment with Masti Veyxym® in nonsevere CM cases may constitute an alternative therapy to reduce antibiotics. However, noninferiority evaluations were mostly inconclusive. Further investigations with a larger sample size are required to confirm the results and to make a clear statement on noninferiority.
TL;DR: The time needed for meloxicam to no longer be detected in milk of the TRT group was longer compared to the PC group, indicating that a longer milk withdrawal is needed, and data suggest higher bioavailability as the underlying mechanism.
Abstract: The objective of this study reported here was determine whether differences occurred in meloxicam pharmacokinetics between postpartum cows and mid-lactation cows. Preliminary data from a separate study (P. J. Gorden, unpublished data) in postpartum cows demonstrated elevated plasma and milk concentration profiles compared to previously published data (Malreddy, Coetzee, KuKanich, & Gehring, ). Two different groups were enrolled, each with 10 cows. The treatment group (TRT) was postpartum cows treated with meloxicam, and the positive control (PC) group was cows in mid-lactation treated with meloxicam. Plasma and milk meloxicam concentrations between the TRT and PC group were compared. Significant differences in meloxicam concentration in plasma were determined at all time points from 8 hr to 120 hr post-treatment. In milk, there was a treatment (p = .003), time (p < .001), and treatment by time interaction (p < .001). Significant differences in milk meloxicam concentration were determined at all time points from 8 hr to 96 hr post-treatment, except for the 16-hr time point. The time needed for meloxicam to no longer be detected in milk of the TRT group was longer compared to the PC group, indicating that a longer milk withdrawal is needed. These data suggest higher bioavailability as the underlying mechanism. Further research is needed to determine the mechanisms underlying differences this outcome.
TL;DR: Transdermal flunixin meglumine was administered to 10 adult Holstein cows in their second or third lactation at the label dose of 3.33 mg/kg every 24 hr for three total treatments, and the mean accumulation factor was 1.10 after three doses, indicating changes in dosing may not be required when giving multiple doses of flunxin transdermal.
Abstract: A transdermal formulation of the nonsteroidal anti-inflammatory drug, flunixin meglumine, has been approved in the United States and Canada for single-dose administration. Transdermal flunixin meglumine was administered to 10 adult Holstein cows in their second or third lactation at the label dose of 3.33 mg/kg every 24 hr for three total treatments. Plasma flunixin concentrations were determined using high-pressure liquid chromatography with mass spectroscopy (HPLC-MS). Pharmacokinetic analysis was completed on each individual animal with noncompartmental methods using computer software. The time to maximum drug concentration (Tmax) was 2.81 hr, and the maximum drug concentration was 1.08 μg/ml. The mean terminal half-life (T½) was determined to be 5.20 hr. Clearance per fraction absorbed (Cl/F) was calculated to be 0.294 L/hr kg-1 , and volume of distribution of fraction (Vz/F) absorbed was 2.20 L/kg. The mean accumulation factor was 1.10 after three doses. This indicates changes in dosing may not be required when giving multiple doses of flunixin transdermal. Further work is required to investigate the clinical efficacy of transdermal flunixin after multiple daily doses.