A physiologically based pharmacokinetic model for oxytetracycline residues in sheep

A physiologically based pharmacokinetic model (PBPK) for oxytetracycline (OTC) residues in sheep was developed using previously published data from a combined serum pharmacokinetic and tissue residue study [Craigmill et al. (2000) J. Vet. Pharmacol. Ther.23, 345]. Physiological parameters for organ weights and tissue blood flows were obtained from the literature. The tissue/serum partition coefficients for OTC were estimated from the serum and tissue residue data obtained at slaughter. The model was developed to include all of the tissues for which residue data were available (serum, kidney, liver, fat, muscle and injection site), and all of the remaining tissues were combined into a slowly perfused compartment with low permeability. Total body clearance of OTC calculated in the previous study was used as the starting value for clearance in the PBPK model, with the kidney being the only eliminating organ. The model was built using ACSL (Advanced Continuous Simulation Language) Graphic Modeler, and the model was fit to the serum and tissue data using the ACSL Math/Optimizer software (AEgis Technologies Group, Inc., Huntsville, AL, USA). A sensitivity analysis was also performed to determine which parameters had the greatest effect on the goodness of fit. Numerous strategies were tested to model the injection site, and a model providing a biexponential absorption of the drug from the injection bolus gave the best fit to the experimental data. The model was validated using the clearance parameters calculated from the traditional pharmacokinetic model for each individual animal in the PBPK model. This simple PBPK model well predicted OTC residues in sheep tissues after intramuscular dosing with a long-acting preparation and may find use for other species and other veterinary drugs.     

A PBPK model for midazolam in four avian species

A physiologically based pharmacokinetic (PBPK) model was developed for midazolam in the chicken and extended to three other species. Physiological parameters included organ weights obtained from 10 birds of each species and blood flows obtained from the literature. Partition coefficients for midazolam in tissues vs. plasma were estimated from drug residue data obtained at slaughter. The avian models include separate compartments for venous plasma, liver, kidney, muscle, fat and all other tissues. An estimate of total body clearance from an earlier in vitro study was used as a starting value in the model, assuming almost complete removal of the parent compound by liver metabolism. The model was optimized for the chicken with plasma and tissue data from a pharmacokinetic study after intravenous midazolam (5 mg/kg) dose. To determine which parameters had the most influence on the goodness of fit, a sensitivity analysis was performed. The optimized chicken model was then modified for the turkey, pheasant and quail. The models were validated with midazolam plasma and tissue residue data in the turkey, pheasant and quail. The PBPK models in the turkey, pheasant and quail provided good predictions of the observed tissue residues in each species, in particular for liver and kidney.     

Comparative response of swine and rats to high-fiber or high-protein diets

Twenty-four growing swine and 24 growing rats were fed high-protein (34%) diets on an ad libitum basis to determine their effects on body weight, carcass characteristics, intestinal microbiological profile and visceral organ weights. High dietary fiber reduced body weight gain and gain:feed ratio in both swine and rats and decreased body fatness in swine; it increased relative kidney weight (percentage of body weight) in both swine and rats and decreased relative liver weight in rats but increased it in swine. Absolute weights of stomach and large intestine were unaffected by high fiber in either species, but relative weight of small and large intestine was increased in swine and relative weight of stomach was increased in rats. High dietary protein increased absolute and relative weights of kidneys in both species and increased relative liver in swine but not in rats. Absolute weight of large intestine was increased by high dietary protein in rats and tended to be increased in swine; relative large intestine weight was increased in both species. The microbial profile of large intestinal contents of rats showed no effect of diet on Enterobacteriaceae, Campylobacter, Salmonella or total anaerobes and cellulolytic organisms, but coliforms were higher in rats fed high fiber or high protein than in controls. We conclude that dietary levels of fiber and protein influence growth of specific segments of the gastrointestinal tract of growing rats and swine, probably by different mechanisms of action.     

生理药动学模型及其在兽医药理学研究中的应用

生理药动学模型是一种模拟机体循环系统的血液流向,将各器官或组织相互联结起来而建立的整体模型,和经典房室模型与统计矩原理相比,生理模型有其独特的优越性.建立药动学生理模型的主要步骤包括收集资料、设计血流图、建立物质平衡方程组、验证和修订模型.目前,国内外学者已开展了数十种化合物在动物或人体内的生理药动学模型研究.生理模型在开展兽医药动-药效模型研究、指导兽药临床合理应用、指导新兽药的研发、评估兽药残留风险等方面具有良好的应用前景.     

Development of a physiologically based pharmacokinetic model to predict tulathromycin distribution in goats

Physiologically based pharmacokinetic (PBPK) models, which incorporate species- and chemical-specific parameters, could be useful tools for extrapolating withdrawal times for drugs across species and doses. The objective of this research was to develop a PBPK model for goats to simulate the pharmacokinetics of tulathromycin, a macrolide antibiotic effective for treating respiratory infections. Model compartments included plasma, lung, liver, muscle, adipose tissue, kidney, and remaining poorly and richly perfused tissues. Tulathromycin was assumed to be 50% protein bound in plasma with first-order clearance. Literature values were compiled for physiological parameters, partition coefficients were estimated from tissue:plasma ratios of AUC, and the remaining model parameters were estimated by comparison against the experimental data. Three separate model structures were compared with plasma and tissue concentrations of tulathromycin in market age goats administered 2.5 mg/kg tulathromycin subcutaneously. The best simulation was achieved with a diffusion-limited PBPK model and absorption from a two-compartment injection site, which allowed for low persistent concentrations at the injection site and slower depletion in the tissues than the plasma as observed with the experimental data. The model with age-appropriate physiological parameters also predicted plasma concentrations in juvenile goats administered tulathromycin subcutaneously. The developed model and compilation of physiological parameters for goats provide initial tools that can be used as a basis for predicting withdrawal times of drugs in this minor species.     

A physiologically based pharmacokinetic model for chickens exposed to feed supplemented with monensin during their lifetime

We developed a flow‐limited physiologically based pharmacokinetic model for residues of monensin in chickens and evaluated its predictive ability by comparing it with an external data set describing concentration decays after the end of treatment. One advantage of this model is that the values for most parameters (34 of 38) were taken directly from the literature or from field data (for growth and feed intake). Our model included growth (changes in body weight) to describe exposure throughout the life of the chicken. We carried out a local sensitivity analysis to evaluate the relative importance of model parameters on model outputs and revealed the predominant influence of 19 parameters (including three estimated ones): seven pharmacokinetic parameters, five physiological parameters and seven animal performance parameters. Our model estimated the relative bioavailability of monensin as feed additive at 3.9%, which is even lower than the absolute bioavailability in solution (29.91%). Our model can be used for extrapolations of farming conditions, such as monensin supplementation or building lighting programme (which may have a significant impact for short half‐life molecules such as monensin). This validated PBPK model may also be useful for interspecies extrapolations or withdrawal period calculations for modified dosage regimens.     

Mathematical modeling and simulation in animal health – Part II: principles,methods, applications,and value of physiologically based pharmacokinetic modeling in veterinary medicine and food safety assessment

This review provides a tutorial for individuals interested in quantitative veterinary pharmacology and toxicology and offers a basis for establishing guidelines for physiologically based pharmacokinetic (PBPK) model development and application in veterinary medicine. This is important as the application of PBPK modeling in veterinary medicine has evolved over the past two decades. PBPK models can be used to predict drug tissue residues and withdrawal times in food‐producing animals, to estimate chemical concentrations at the site of action and target organ toxicity to aid risk assessment of environmental contaminants and/or drugs in both domestic animals and wildlife, as well as to help design therapeutic regimens for veterinary drugs. This review provides a comprehensive summary of PBPK modeling principles, model development methodology, and the current applications in veterinary medicine, with a focus on predictions of drug tissue residues and withdrawal times in food‐producing animals. The advantages and disadvantages of PBPK modeling compared to other pharmacokinetic modeling approaches (i.e., classical compartmental/noncompartmental modeling, nonlinear mixed‐effects modeling, and interspecies allometric scaling) are further presented. The review finally discusses contemporary challenges and our perspectives on model documentation, evaluation criteria, quality improvement, and offers solutions to increase model acceptance and applications in veterinary pharmacology and toxicology.     

Development of a multiroute physiologically based pharmacokinetic model for orbifloxacin in rabbits

To predict the orbifloxacin concentrations in rabbits after multiple routes of administration, a flow‐limited multiroute physiologically based pharmacokinetic (PBPK) model was developed. Three routes of administration (IV, IM, and PO) were incorporated into this model. Physiological parameters including tissue weights and blood flows through different tissues were obtained from the literature. The tissue/plasma partition coefficients (P_Xs) for noneliminating tissues were calculated according to the area method, while the P_Xs for kidney and the rest of the body compartment, together with other parameters for absorption and elimination, were optimized based on the published concentrations. The comparisons between predicted and observed orbifloxacin concentrations proved its validity, and the present model predicted available concentration data well, including those in liver, kidney, muscle, lung, heart, and plasma after oral, intravenous, or intramuscular administration. A local sensitivity analysis was also performed, which showed that the parameters for oral absorption were most influential on the orbifloxacin concentrations. This model was used to predict plasma and tissue concentrations after multiple oral or intramuscular administration. This study demonstrated the feasibility of predicting drug residues in minor species after multiple routes of administration in the extra‐label manner using the PBPK modeling.     

Multi-breed genetic evaluation in a Gelbvieh population

A multi-breed model was presented for the genetic evaluation of growth traits in beef cattle. In addition to the fixed effects, random direct and maternal genetic effects, and random maternal permanent environmental effects are considered; the model also fits direct and maternal heterosis and direct and maternal breed-of-founder (BOF) x generation group effects using a Bayesian approach that weights prior literature estimates relative to information supplied by the dataset to which the model will be applied. The multi-breed evaluation procedures also allow the inclusion of external evaluations for animals of other breeds. The multi-breed model was applied to a dataset provided by the American Gelbvieh Association. Different analyses were conducted by varying the weights given to the prior literature relative to the information provided by the dataset. Large differences were observed for the heterosis estimates, the BOF x generation group effect estimates, and the predicted breeding values across breeds due to the weights posed on prior literature estimates versus estimates derived directly from data. However, the rankings within breed were observed to be relatively robust to the different weights on prior information.     

A rapid method for determining normal weights of medium-to-large mongrel dogs

The length, circumference, height and weight of 63 (29 female, 34 male) unconditioned mongrel dogs were measured. Means and standard deviations of the mean were calculated for each parameter for males, females, and combined totals. Combined totals were used to plot regression lines for length: weight, circumference: weight, and height: weight. Correlation coefficients of the lines of regression were 0.76, 0.85, and 0.41 for length: weight, circumference: weight, and height: weight, respectively, and standard errors for the three parameters were 3.20, 2.25, and 3.95, respectively. Circumference, the best single parameter for predicting weight, was selected and used to compile a table of normalized weights expressed in kilograms and pounds for convenient comparison.     

影响五指山小型猪主要脏器重量及脏器系数的因素分析

为测定不同年龄段封闭群五指山小型猪主要脏器重量和脏器系数,研究影响脏器系数的因素,试验选用普通级封闭群五指山小型猪74头(其中♂43头,♀31头),测定体重和心脏、肝脏、肺脏、脾脏、肾脏、胃6个脏器的重量,计算脏器系数,分别以年龄和体重为研究因素,对脏器重量和脏器系数进差异性、相关和回归分析。性别间比较显示,不同年龄段小型猪脏器重量少量脏器间存在显著性差异(P<0.05),但脏器系数性别间差异不显著(P＞0.05)。单因素分析结果显示,随着年龄和体重的增大,脏器重量显著增加(P<0.0001);在脏器系数对年龄因素的分析中,心脏、肝脏、肺脏和胃出现显著减小的趋势(P<0.0001),而脾脏和肾脏的减小趋势不明显(P＞0.05),而在脏器系数对体重因素的分析中,所有脏器系数均出现明显减小的趋势(P<0.01)。多因素分析结果显示,各脏器的重量和脏器系数受体重的影响程度不同。研究结果表明,性别因素对五指山小型猪脏器重量和脏器系数的影响不大,年龄和体重是主要的影响因素,其中体重因素最为关键,脏器重量随着体重的增加而显著增加,而脏器系数明显减小。     

Abattoir condemnation due to parasitic infections and its economic implications in the region of Trikala,Greece

The prevalence of parasitic infections responsible for the condemnation of carcasses and viscera during meat inspection, and their economic implication, was estimated in a year long abattoir survey of 10 277 slaughtered farm animals in the region of Trikala, Greece. The organs examined for the presence of parasitic lesions during meat inspection were: liver and lungs of all animals, rumen of cattle, small intestine of lambs and kids, and muscles of cattle and swine. The parasitic lesions observed in the lungs of cattle, sheep and goats were caused only by hydatid cysts. No hydatid cysts were observed in the lungs of swine. The parasitic lesions observed in the liver of cattle, sheep and goats were as a result of hydatid cysts and flukes of Fasciola hepatica and Dicrocoelium dendriticum, while those of swine were due to milk spots only. Moniezia sp. proglottids were found in the small intestine of lambs only. The prevalence of parasites responsible for the condemnation of marketable organs was low (0.26%). Parasites were responsible for 22% of the total of condemned organs, and their annual cost was 99, 00 GDR (approximately 292 Euros). The parasites most contributing to marketable organ condemnation were hydatid cysts (26%) and D. dendriticum flukes (26%).     

Minimum space allowance for transportation of swine by road

Space allowance for animals in transit is a consistent concern in many countries that are developing codes of practice and regulations to assure humane treatment of food producing animals. The minimum space allowance requirements for a broad size range of swine in transit has not been well described or scientifically substantiated. A maximal loading pressure recommendation for pigs weighing from 5 to 250 kg was derived by a consultative process involving the swine transportation industry, animal welfare groups, and a literature review. The recommended maximal loading pressure under ideal conditions for swine loaded in groups can be described as a hoerl model y = (37.53)(0.9969)w(W0.5008), where y = loading pressure in kg body weight/m2 and W = average animal body weight in kilograms.     

Abattoir Condemnation due to Parasitic Infections and its Economic Implications in the Region of Trikala,Greece

The prevalence of parasitic infections responsible for the condemnation of carcasses and viscera during meat inspection, and their economic implication, was estimated in a year long abattoir survey of 10 277 slaughtered farm animals in the region of Trikala, Greece. The organs examined for the presence of parasitic lesions during meat inspection were: liver and lungs of all animals, rumen of cattle, small intestine of lambs and kids, and muscles of cattle and swine. The parasitic lesions observed in the lungs of cattle, sheep and goats were caused only by hydatid cysts. No hydatid cysts were observed in the lungs of swine. The parasitic lesions observed in the liver of cattle, sheep and goats were as a result of hydatid cysts and flukes of Fasciola hepatica and Dicrocoelium dendriticum, while those of swine were due to milk spots only. Moniezia sp. proglottids were found in the small intestine of lambs only. The prevalence of parasites responsible for the condemnation of marketable organs was low (0.26%). Parasites were responsible for 22% of the total of condemned organs, and their annual cost was 99 500 GDR (～€292). The parasites most contributing to marketable organ condemnation were hydatid cysts (26%) and D. dendriticum flukes (26%).     

Noroviruses and sapoviruses in man and farm animals

Noro- and Sapoviruses belong to the virus family Caliciviridae and are important causative agents of acute epidemic gastroenteritis in man. In many cases transmission of Noro- and Sapoviruses occurs via contaminated food or water and the respective diseases are therefore designated as food borne. Recently, the presence of Noro- and Sapoviruses in farm animals has attracted increasing attention. Clinical symptoms were observed after experimental infection of cattle and swine with members of the two virus groups. Thus far it is not known, whether virus transmission from animals to man does occur.     

Phenotypic and genetic variation in body weight,food intake and energy utilisation in Hereford cattle II. Effects of age and length of performance test

The effects of length of test, age when evaluations are made, and correction of data for body weightat the start of test on genetic and phenotypic parameters describing performance test results in beef cattle were studied. The data consisted of body weight, food intake and carcass composition measurements on 542 Hereford bull calves, from 200 to 400 days of age. The traits studied included weights at various ages, weight gain, lean growth rate, food intake, food conversion ratio, lean food conversion ratio, food intake in relation to metabolic body weight, energy required for protein and fat deposition, and predicted maintenance expenditure. Traits were derived for the whole test as well as for part test periods of 200–300 days and 300–400 days.Heritabilities for all traits, except those describing weight at a given age, were lower for the 300–400-day period than for either the 200–300-day period or the whole test. Correlations, however, were higher between whole test and 300–400-day traits than between whole test and 200–300-day traits. Phenotypic correlations between the same trait measured in the two-part test period were very low and much lower than the genetic correlations. Corrections for body weight at the start of test had only a trivial effect on the heritabilities of all traits, the relationships between traits and potential genetic progress in traits measured during the test.     

A Livestock Disease Survey from Auction Mart Inspection in Saskatchewan

The data on health problems from visual livestock inspection at an auction mart in Saskatchewan during a two year period were tabulated for swine, cattle and calves. The major conditions seen in swine were underweight animals, infectious diseases or congenital abnormalities. Infectious diseases such as Hypoderma spp. infestations, ringworm or eye infections were the primary troubles in older cattle. Young calves demonstrated a predominance of congenital (herniation) and infectious (enteritis or navel infection) diseases.     

“增乳健牛散”对小鼠的亚急性毒性试验

为了测定增乳健牛散（生乳散）的亚急性毒性反应，取昆明小鼠为试验动物，随机分组，以临床应用剂量的2、4、8倍饲喂给药，确定增乳健牛散（生乳散）在28d内对小鼠的亚急挫毒性反应。结果表明，各试验组小鼠全部健活，体征、体重、外观、行为、采食量及饲料利用率、脏器系数、血液生理生化指标、脏器结构均无异常。增乳健牛散（生乳散）对受试动物未见明显的亚急性毒性反应。     

抗球虫中药散剂常青散的亚急性毒性试验

为了测定抗球虫中药散剂常青散的亚急性毒性反应,取昆明小鼠为试验动物,随机分组,以临床应用剂量的2、4、8倍饲喂给药,确定常青散在28天内对小鼠的亚急性毒性反应。结果表明各试验组小鼠全部健活,体征、体重、外观、行为、采食量及饲料利用率、脏器系数、血液生理生化指标、脏器结构均无异常。常青散对受试动物未见有明显的亚急性毒性反应。     

Farmer estimation of live bodyweight of cattle: implications for veterinary drug dosing in East Africa

The ability of smallholder farmers and animal health workers to estimate live bodyweight can critically affect the likelihood of under- or over-dosing of veterinary compounds in decentralised systems where farmers administer a significant proportion of the veterinary treatments. A survey of 324 cattle owned by 170 farmers was conducted in Busia District, Kenya. Cattle were weighed on a standard calibrated scale and owners were asked to estimate the live weight of their animals. Weights were also estimated by a weigh-band and by local animal health workers.Cattle owners consistently underestimated the weights of their cattle; 85.7% of the cattle had their bodyweights underestimated by an average of 46.9% of their true weight. Furthermore, very few cattle (19.0%) had their weights estimated accurately to within ±20% of their true weight by these farmers, an accuracy range important for drug dosing. This finding raises concerns of widespread under-dosing of cattle with trypanocidal and other veterinary drugs. Animal health workers were better at estimating live bodyweight of cattle; 76.6% of cattle were estimated accurately to within ±20% of their true weight.It is possible to improve farmers’ and animal health workers’ ability to estimate accurately live bodyweight of cattle with appropriate training. Evidence of this was provided by animal health workers whose estimates improved over time as they received feedback of the true weights of different sizes of cattle from the standard scale.