Drug disposition in the neonatal animal, with particular reference to the foal

Differences between neonatal and adult animals in their response to drugs can usually be attributed to altered disposition (ie, distribution, metabolism and excretion) processes during the neonatal period. These alterations affect the plasma concentrations as well as the concentrations of drug attained at the receptor site. Some characteristics of the neonatal period include greater absorption from the gastrointestinal tract, lower extent of plasma protein binding, increased apparent volume of distribution of drugs that distribute in extracellular fluid or total body water, increased permeability of the 'blood-brain' barrier and slower elimination of many drugs. The hepatic microsomal oxidative reactions and glucuronide conjugation are deficient metabolic pathways for a varying period of time, usually up to six weeks after birth or even longer in some species. Decreased metabolism can affect the duration of action of lipid-soluble drugs. Functional immaturity of the kidneys decreases the renal excretion of polar drugs and drug metabolites. Overall renal function appears to reach maturity within two weeks after birth in ruminant species and pigs, while maturation may take at least four weeks in other species of domestic animals. Considerable physiological and biochemical development takes place during the first five days after birth with maturation continuing more slowly over the succeeding five weeks. The time it takes for any process to reach functional maturity depends on the process in question and varies with the species of animal. The absorption, disposition and pharmacological response to drugs during the first 24 h after birth may be unique to that time and, because of lack of information, are impossible to predict.(ABSTRACT TRUNCATED AT 250 WORDS)     

Application of risk assessment and management principles to the extralabel use of drugs in food-producing animals

A risk assessment of the food safety implications of drugs used in food-producing animals is an essential component of the regulatory approval process for products containing these drugs. This ensures that there is negligible risk to human health if these drugs are used according to the instructions that appear on the approved label. A relative paucity of approved products for veterinary species; however, forces veterinarians worldwide to use drugs in an extralabel manner to treat disease and alleviate suffering in animals. In food-producing animals, this may result in residues that are potentially harmful to the human consumer. This review describes how risk assessment principles can be extended to evaluate the risks posed by different classes of extralabel drug use. Risk management practices in the United States and Europe are summarized and contrasted to illustrate the application of these principles.     

Immunomodulators for prevention and treatment of infectious diseases in food-producing animals.

The goal of immunomodulation in food-producing animals is to regulate immunity for the benefit of the animal and production efficiency. Immunomodulators are substances that exert this control and include cytokines, pharmaceuticals, microbial products, nutraceuticals, and traditional medicinal plants. Although treatment and prevention of infectious diseases are the most common reasons to use immunomodulators, other conditions, such as amelioration of stress-induced immunosuppression, maturation of the neonate's developing immune response, and strategies to reduce the metabolic cost of eliciting an immune response also are well suited for immunomodulation. Continued discovery of new immune regulators and increased understanding of immunity in food-producing animals will ensure new opportunities for the use of immunomodulators in food-producing animals.     

New drugs for horses and production animals in 2010

In 2010, three new active pharmaceutical ingredients were released on the German market for horses and food-producing animals. These were gamithromycin (Zactran?), a new macrolide antibiotic, Monepantel (Zolvix?), a broad spectrum anthelmintic with a novel mechanism, and Pergolide (Prascend?), the first dopamine receptor agonist for animals. Two substances have been approved for additional species. The tetracycline antibiotic doxycycline is now also authorized for turkeys and the nonsteroidal anti-inflammatory drug firocoxib from the group of cyclo-oxygenase-2 (COX-2) inhibitors is now available for horses. Furthermore, four new preparations with an interesting new pharmaceutical form, one drug with a new formulation and two drugs, which are interesting because of other criteria, were added to the market for horses and food producing animals.     

Peculiarities of pharmacokinetics in young animals

In young animals, especially in newborns, absorption, distribution, metabolism and elimination of drugs differ markedly from adults. Respective differences and the cause of these differences are described, including some examples of drug pharmacokinetics in young and adult animals of different species. However, the estimation of pharmacokinetic differences and their pharmacological consequences in young animals is not generally possible, because published data on characteristics of pharmacokinetics in young animals are available only for relatively few drugs. Furthermore, such estimation is complicated by an interaction of different pharmacokinetic processes. Thus, a generally accepted adaptation of dosage schedules for drugs in young animals cannot be offered as yet. In any event, veterinarians should consider the age-dependency of drug pharmacokinetics when drugs, dosages and dosage intervals for treatment of young animals are chosen.     

Mathematical modeling and simulation in animal health. Part III: Using nonlinear mixed‐effects to characterize and quantify variability in drug pharmacokinetics

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.     

Some aspects of clinical pharmacokinetics in veterinary medicine. I

This series of two review articles deals with general aspects of the mechanisms which govern absorption and distribution of drugs within the body, and the kinetics of drug metabolism and excretion. Emphasis is given to the verification of pharmacokinetic principles in domestic animals, and the clinical applications which proceed therefrom. In the first part, the concept of the two compartment and three compartment models for drug disposition are introduced and developed to demonstrate the mathematical models which may be derived to describe the kinetics of drug distribution and elimination. In the second part bioavailability and drug dosage will be considered.     

Pharmacologic considerations in the management of peripartum conditions in the cow.

As is true with the use of drugs in veterinary medicine in general, there are many controversial issues in the management of peripartum conditions in the cow. For example, the use of PG versus antibacterial drugs in the management of postpartum uterine infections has advocates for the use of either approach. Intrauterine versus systemic administration of antibacterial drugs for the prophylaxis or treatment of postpartum metritis is another area of debate. Clearly, more research is needed in this area. Equally clearly, however, the research results that are available are being disregarded on a daily basis. In considering this discussion of the use of drugs in the peripartum period, one is struck by the frequency that optimum drug therapy of a condition relies on the extralabel use of nonapproved preparations. What guidelines are available to the practitioner in this regard? One example is lack of availability of appropriate dosage regimens or withdrawal times for food derived from treated animals. Unfortunately, pharmacokinetic and residue studies that would aid in establishing guidelines generally are not available and, in most instances, are not forthcoming. Extrapolation of data from other species to the ruminant or extrapolation of information from one drug to a related compound (such as prediction of residue and withdrawal data from an approved aminoglycoside, dihydrostreptomycin, to another unapproved drug, gentamicin) is fraught with difficulties. The need for research in this area is obvious, and lack of such information is one of the major dilemmas in trying to establish rational drug therapy in the food-producing animal. Recent developments in drug therapy have led to innovative approaches for the management of peripartum and other diseases in cattle. The use of PG in the treatment of reproductive disorders, so commonplace and widely accepted in contemporary veterinary practice, is a relatively recent approach that continues to be refined with the development of new, more potent, more specific PG analogs. What will be the role of ceftiofur, a potent, third-generation cephalosporin that currently is approved only for the treatment of respiratory infections in cattle, in the management of reproductive tract infections? The fluoroquinolones, which represent a novel approach to the control of infectious diseases, are being increasingly used in veterinary and human medicine, and one may predict that these powerful antimicrobial drugs will find application in bovine practice, including for the treatment of peripartum infections. Pharmacologic manipulation of immune and defense mechanisms also is an approach with some promise.(ABSTRACT TRUNCATED AT 400 WORDS)     

ABCG2 transporter: therapeutic and physiologic implications in veterinary species

Drug transporters significantly influence drug pharmacokinetics and pharmacodynamics. While P-glycoprotein, the product of the MDR1 (ABCB1) gene, is the most well-characterized ABC transporter, the pharmacological importance of a related transporter, ABCG2, is starting to be realized in veterinary medicine. Based primarily on human and rodent studies, a number of clinically relevant, structurally and functionally unrelated drugs are substrates for ABCG2. ABCG2 is expressed by a variety of normal tissues including the intestines, renal tubular cells, brain and retinal capillary endothelial cells, biliary canalicular cells, and others, where it functions to actively extrude substrate drugs. In this capacity, ABCG2 limits oral absorption of substrate drugs and restricts their distribution to privileged sites such as the brain and retina. ABCG2 is also expressed by tumor cells where it functions to limit the intracellular accumulation of cytotoxic agents, contributing to multidrug resistance. Several ABCG2 polymorphisms have been described in human patients, some of which result in altered drug disposition, increasing susceptibility to adverse drug reactions. Additionally, ABCG2 polymorphisms in humans have been associated with disease states such as gout. Feline ABCG2 has recently been demonstrated to have several amino acid differences at conserved sites compared with 10 other mammalian species. These amino acid differences adversely affect transport function of feline ABCG2 relative to that of human ABCG2. Furthermore, these differences appear to be responsible for fluoroquinolone-induced retinal toxicity in cats and may play a role in acetaminophen toxicity as well. Studies in rodents and sheep have determined that ABCG2 expressed in mammary tissue is responsible for the secretion of many compounds (both therapeutic and toxic) into milk. Finally, data in rodent models suggest that ABCG2 may play an important role in regulating a number of physiologic pathways involved in protecting erythrocytes from oxidative damage.     

beta-Lactam resistance and beta-lactamases in bacteria of animal origin

beta-Lactams are among the most clinically important antimicrobials in both human and veterinary medicine. Bacterial resistance to beta-lactams has been increasingly observed in bacteria, including those of animal origin. The mechanisms of beta-lactam resistance include inaccessibility of the drugs to their target, target alterations and/or inactivation of the drugs by beta-lactamases. The latter contributes predominantly to beta-lactam resistance in Gram-negative bacteria. A variety of beta-lactamases have been identified in bacteria derived from food-producing and companion animals and may further serve as a reservoir for beta-lactamase-producing bacteria in humans. While this review mainly describes beta-lactamases from animal-derived Escherichia coli and Salmonella spp., beta-lactamases from animal-derived Campylobacter spp., Enterococcus spp., Staphylococcus spp. and other pathogens are also discussed. Of particular concern are the increasingly-isolated plasmid-encoded AmpC-type CMY and extended-spectrum CTX-M beta-lactamases, which mediate acquired resistance to extended-spectrum beta-lactams. The genes encoding these enzymes often coexist with other antimicrobial resistance determinants and can also be associated with transposons/integrons, increasing the potential enrichment of multidrug resistant bacteria by multiple antimicrobial agents as well as dissemination of the resistance determinants among bacterial species. Characterization of beta-lactam-resistant animal-derived bacteria warrants further investigation of the type and distribution of beta-lactamases in bacteria of animal origin and their potential impact on human medicine.     

食品动物兽药残留试验注册资料评审主要内容及常见问题

食品动物使用兽药后,肉蛋奶等动物性食品中兽药残留对消费者可能产生毒害作用,影响人类健康和消费安全,因此,控制动物性食品中兽药残留问题已成为兽药研发和保障食品安全的重要内容。食品动物兽药残留试验资料主要包括兽药最大残留限量标准、兽药残留检测方法标准和休药期确定三个方面内容。本文结合近年来食品动物兽药残留试验注册资料的评审主要内容及常见问题进行综述,旨在为食品动物用兽药的研发与注册提供参考。     

Pharmacokinetics in immature animals: a review.

Differences in drug pharmacokinetics between newborn and adult mammals are reviewed. The pharmacokinetic alterations during the maturation process are related to changes in the pattern of absorption, distribution, metabolism, and renal excretion. The most pronounced feature in neonates vs adults is the prolonged elimination half-life of drugs. The main factors causing delayed elimination are under-developed renal clearance and immature metabolism of drugs. Special attention has to be paid to central nervous system depressants and to drugs that are extensively metabolized because they will accumulate with repeated dosing of newborn animals.     

Should licking behavior be considered in the bioavailability evaluation of transdermal products?

Antiparasitic drugs, and especially macrocyclic lactones (MLs), are often formulated as pour-on products because of their ease of administration, convenience, and reduction of stress in treated animals. However, because of self- and allo-grooming, much of a drug administered transdermally may be systemically absorbed via the oral route, creating highly variable pharmacokinetic and pharmacodynamic response in treated (and untreated) animals. Testing bioequivalence (BE) of pour-on drugs in cattle under laboratory conditions (with restricted licking) ignores a major factor of drug disposition of these drugs and thus fails to predict therapeutic equivalence in the target population under clinical conditions of use. Therefore, the interanimal and intra-animal variability associated with licking behavior should be considered as a biological fact, rather than a noise that needs to be reduced or eliminated. As a result, it is recommended that the BE testing for pour-on products in cattle be conducted by evaluating both the mean and distribution of bioavailability parameters between the reference and test products when animals are not prevented from allo- and self-licking.     

Pharmacologic considerations in drug therapy in foals

Rational drug therapy in the foal requires a sound knowledge of the pharmacodynamics and pharmacokinetics of various drugs as well as a thorough understanding of the physiologic differences that exist between the neonate and the adult and that may serve to alter drug disposition and, therefore, drug response. A summary of these physiologic factors with emphasis on the foal is presented and is followed by recommendations regarding the applied therapeutics of various antimicrobial agents.     

The regulatory status of xylazine for use in food-producing animals in the United States

Xylazine is commonly used in veterinary medicine as a tranquillizer or adjunct to surgical anaesthesia. Although its use is approved in companion animals and certain species of deer, xylazine remains unapproved for use in food-producing animals in the United States. This paper reviews existing toxicological and residue chemistry information on xylazine in food animals, particularly cattle, and discusses the regulatory status of the drug in the US, as well as the conclusions reached by the Joint FAO/WHO Expert Committee on Food Additives in its recent evaluation of xylazine.     

Population pharmacokinetics in veterinary medicine: Potential use for therapeutic drug monitoring and prediction of tissue residues

Population pharmacokinetics can be defined as a study of the basic features of drug disposition in a population, accounting for the influence of diverse pathophysiological factors on pharmacokinetics, and explicitly estimating the magnitude of the interindividual and intraindividual variability. It is used to identify subpopulations of individuals that may present with differences in drug kinetics or in kinetic/dynamic responses. Rooted in procedures used in engineering systems, population pharmacokinetics methods were conceived as a means to determine the pharmacokinetic profile in populations in which a sparse number of samples were obtained per individual, such as those in late stage human clinical trials. This is the situation commonly encountered in all aspects of veterinary medicine. The exploratory nature of this technique allows one to probe relationships between clinical factors (such as age, gender, renal function, etc.) and drug disposition and/or effect. Similarly, the utilization of these techniques in the clinical research phases of drug development optimize the determination of efficacy and safety of drugs. Given the observational nature of most studies published so far, statistical methods to validate the population models are necessary. Simulation studies may be conducted to explore data collection designs that maximize information yield with a minimum expenditure of resources. The breadth of this approach has allowed population studies to be more commonly employed in all areas of drug therapy and clinical research. Finally, in veterinary medicine, there is an additional field in which population studies are potentially ideally suited: the application of this methodology to the study of tissue drug depletion and drug residues in production animals, and the establishment of withdrawal times tailored to the clinical or production conditions of populations or individuals. Such application would provide a major step toward assuring a safe food supply under a wide variety of dose and off-label clinical uses. Population pharmacokinetics is an ideal method for generating data in support of the implementation of flexible labelling policies and extralabel drug use recently approved under AMDUCA (Animal Medicinal Drug Use Clarification Act. 21 CFR Part 530).     

Developing new regulatory approaches to antimicrobial safety

Resistance to antimicrobial agents is of concern to public health officials worldwide. In industrialized countries, a significant source of antimicrobial-resistant food-borne infections in humans is the acquisition of resistant bacteria originating from animals. The US Food and Drug Administration (FDA) is committed to resolving the public health impact arising from the use of antimicrobial drugs in food-producing animals. The FDAs goal is to ensure that significant human antimicrobial therapies are not compromised or lost while providing for the safe use of antimicrobials in food animals. Recently the FDA published a guidance document titled 'Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to their Microbiological Effects on Bacteria of Human Health Concern' (US Food and Drug Administration, Center for Veterinary Medicine, 2003). This document outlines a pathway drug sponsors can use to address concerns about antimicrobial resistance prior to approval of their drug. The process uses a qualitative risk assessment approach to assess the potential of the intended use of a product to develop resistance in bacteria that may harm humans. The level of risk determines the level of risk management that is required for the drug to be used. The Food and Drug Administration (FDA) always has the option of not approving a drug if the risk of a public health consequence is too high.     

Future directions in the European union for veterinary education as related to food-producing animals, with special reference to Greece

During the past 50 years, procedures for raising food-producing animals have changed. Intensification of food production was necessary to keep prices low and to fulfill market demands for the continuously increasing worldwide population. Intensification of farming procedures produced many new problems, some of which had a considerable impact on public opinion about how animals are raised and how food of animal origin is produced and preserved. "Man made diseases" of animals such as bovine spongiform encephalopathy (BSE); contamination of foods with dioxins either through contamination of animal feeds or from the environment; and increased microbial resistance to drugs used for treatment, for prophylaxis of animals from infectious agents, and for growth promotion are some well-known hazards of intensified farming. Veterinarians working on food-producing animals are faced with an increased demand for foods of high quality and safety in developed countries, and higher quantities in the rest of the world. These qualitative and quantitative changes indicate that they must adjust to these new conditions. They will be most successful if their education is adjusted to meet the challenges that the public has created for them through new concepts of the production of food of animal origin. One such concept is the production of foods under fully certified procedures from the farm to the consumer's table. Food safety measures protecting public health will better be achieved if the education of the future veterinarian includes the principles of Hazard Analysis Critical Control Points (HACCP) starting at farm level. This article provides some market-driven ideas in this direction for European Union (EU) countries, including Greece.