Toxicity in animals: target species.

The macrocyclic lactone endectocides typified by ivermectin are safe and effective drugs when used according to label directions. However, off-label use, misuse and overdosing can result in toxicity in animal patients as revealed by pharmacovigilance activities. Preclinical toxicity studies demonstrates that the major clinical signs of toxicity are those associated with neurotoxic effects and these are the most common adverse drug reactions noted in overdosed treated animals. Subpopulations of some strains or breeds of some species appear to be uniquely sensitive to the neurotoxic effects of the macrocyclic lactones due to enhanced brain penetration by these drugs as a result of a deficiency in P-glycoprotein arising as a result of a mutation in the MDR1 gene.

Assessment of user safety, exposure and risk to veterinary medicinal products in the European Union.

Safety is an important part of veterinary drug assessment while user safety is a critical part of the overall safety assessment. In the European Union (EU), user safety is addressed through preclinical studies and by relationships with exposure but a key part of the process is the user safety assessment. EU user safety guidelines are available and these make certain recommendations but in places they lack detail and clarity. This paper seeks to examine the relevant factors that lie behind user risk assessments for veterinary medicinal products in general while focusing on EU requirements, the determination of risk management and risk communication strategies and how this relates to user safety assessment and pharmacovigilance responsibilities.

The potential impact of the use of homeopathic and herbal remedies on monitoring the safety of prescription products.

The purpose of this paper is to explore the possibility that adverse reactions and drug interactions arising from the use of homeopathic and herbal medicines could lead to confusion when adverse reactions to conventional medicines are reported. An extensive literature review was conducted on the occurrence of adverse reactions and drug interactions following the use of homeopathic or herbal remedies, and the potential for these to confound adverse event reporting to conventional medicines considered. The survey demonstrates the potential for herbal remedies and homeopathic products, to produce adverse drug reactions or drug interactions, and shows the scope for potential for confusion with those arising from conventional medicines. There is a need for greater awareness that adverse reactions apparently due to a conventional medicine, might in reality be due to a herbal medicine or a drug interaction between a herbal medicine and a conventional drug, particularly when a health professional is unaware of the extent of a patient's self-medication with alternative therapies.

Veterinary pharmacovigilance. Part 1. The legal basis in the European Union.

Pharmacovigilance is a growing discipline and nowhere is this more true than in the context of the legislative requirements for veterinary pharmacovigilance within the European Union (EU), or more specifically, within the European Economic Area. Since 1995, the legislation governing the authorization of veterinary medicinal products in the EU has resulted in the older national procedures being replaced by the mutual recognition procedure and the centralized procedure. Also since 1995, the regulatory requirements for pharmacovigilance have developed and grown, as have the associated guidelines. The recent review of European veterinary medicines legislation, which concluded with the publication of an amending directive and a new regulation in March 2004, has introduced refinements to the pharmacovigilance system. This paper examines the EU legislation governing the authorization of veterinary medicinal products, including the elaboration of maximum residue limits, and the way in which this relates to the requirements of pharmacovigilance.

Veterinary pharmacovigilance. Part 2. Veterinary pharmacovigilance in practice -- the operation of a spontaneous reporting scheme in a European Union country -- the UK, and schemes in other countries.

Veterinary pharmacovigilance, as it operates in the European Union (EU), covers a very broad remit, including adverse effects in treated animals, exposed humans and the environment, and in addition, it extends to cover the violation of maximum residue limits. The mainstay of veterinary pharmacovigilance is the spontaneous reporting scheme working along side other systems such as those reporting on residues surveillance. One of the most well established schemes in the EU is that operating in the UK and this paper examines the evolution of that scheme and some of its findings, data from other countries, and information available from the literature. It also tentatively examines the ways that pharmacovigilance can be used for regulatory purposes, and the contribution from pharmacoepidemiology.

Veterinary pharmacovigilance. Part 3. Adverse effects of veterinary medicinal products in animals and on the environment.

Like humans, animals may experience adverse effects when treated with medicinal products. These effects may be related to the pharmacological or toxicological properties of the substances used or they may arise because of hypersensitivity. Veterinary medicinal products may also possess the ability to harm the environment. This paper reviews the potential of veterinary medicinal products to cause adverse effects in animals and on the environment.

Veterinary pharmacovigilance. Part 4. Adverse reactions in humans to veterinary medicinal products.

Although seemingly rare, adverse reactions to veterinary products do occur. These may arise from inadvertent exposure during use or as a result of occupational accidents. They are often mild in nature and include adverse effects such as minor skin reactions. However, more serious reactions may occur, and they are not restricted to the effects of the veterinary medicines themselves. For example, high-pressure injection injuries may occur as a result of accidents occurring during animal vaccination operations. This paper reviews some of these events, mentions where appropriate the regulatory actions taken, and describes some of the measures used to minimise such effects in the future, and serves to bring the issues discussed here to the attention of pharmacologists, pharmacoepidemiologists and others who train those who use veterinary medicinal products.

Veterinary pharmacovigilance. Part 5. Causality and expectedness.

In the European Union and elsewhere there is a requirement to ascribe causality to adverse drug reactions which occur in treated animals. In the EU, the ABON system of causality assessment is used but the assignment of causality assigned is not always self evident, and it may be complicated for a variety of reasons. In this paper, the approaches to causality assessment, based on a number of key criteria which examine the administration of the drug in relation to the sequence of ensuing events and the presence of biological plausibility are examined, along with the utility of using algorithms to facilitate this process. Unexpected adverse drug reactions usually require expedited reporting, depending on national or regional regulatory requirements. Again, deciding on what might constitute an expected (or unexpected) adverse reaction, particularly when a product may be intended for use in a number of species, and when within any one species a number of breeds may be treated, is not necessarily a straightforward issue. However, an approach to facilitate the decision- making process, based on a similar approach used in the pharmacovigilance of human medicinal products is discussed.

Veterinary pharmacovigilance. Part 6. Predictability of adverse reactions in animals from laboratory toxicology studies.

Toxicological studies are conducted on constituents of veterinary medicinal products for a number of reasons. Aside from being a requirement of legislation, they are carried out for predictive purposes in the assessment of user safety or for the determination of consumer safety, for example, in the elaboration of maximum residue limits or tolerances. Alternatively, the results of toxicology studies may be available as they have been generated for registration of the drug for human medicinal purposes. This paper examines if the results of such studies have any predictive value for adverse reactions, which might occur during clinical use in animals. A number of adverse reactions, notably the Type A (toxicology or pharmacology dependent) should be predictable from these laboratory studies. However, as with human pharmaceutical products, they have less utility in predicting Type-B reactions (idiosyncratic in nature).

The use of microbiological end-points in the safety evaluation and elaboration of maximum residue limits for veterinary drugs intended for use in food producing animals.

The safety evaluation of veterinary drugs intended for use in food producing animals relies heavily on the results of toxicity studies in laboratory animals, supported where possible by any data resulting from human exposure. The general approach involves the calculation of an acceptable daily intake which in turn can be used to elaborate maximum residue limits. It is an approach used in the European Union, in other countries and at the international level. In recent years, concern has been expressed over the presence of microbiologically active residues of veterinary drugs in food and their possible effects on the human gastrointestinal microflora. Methodologies for conducting microbiological safety studies have been investigated and approaches to microbiological safety assessments have been debated. The whole approach has proved to be controversial, partly because there are considerable doubts over the ability of low concentrations of antibiotic substances to produce adverse effects on the human gut flora and partly because there are no validated methods for testing for these attributes. This paper reviews the problems in some detail and discusses the regulatory consequences.

Ranking of chemicals for carcinogenic potency--a comparative study of 13 carcinogenic chemicals and an examination of some of the issues involved.

A number of methods for categorization of carcinogens, including classification and ranking, have been examined and applied to 13 carcinogenic chemicals. Compounds known to be carcinogenic to humans ranked highly in the ranking systems. The TD50 approach was a satisfactory ranking system. The examination of the classification system of the International Agency for Research on Cancer, and the studies of the ranking systems revealed the importance of considering the underlying mechanisms of carcinogenesis. Some of the important problems of categorizing carcinogens are discussed.

Hypersensitivity in humans and exposure to veterinary drugs.

There is a small but unquantifiable risk that residues of hypersensitivity-inducing drugs may elicit hypersensitivity reactions in human consumers of food of animal origin. The levels present are unlikely to be sufficient to cause initial sensitization, and this is most likely to occur by therapeutic use in man. However, these levels may occasionally elicit hypersensitivity reactions in previously sensitized patients. The available data suggests that the incidences of such reactions are exceedingly low and the risk can be minimised by the careful use and observance of withdrawal periods. Occupational exposure may present a higher, but again unquantifiable risk which may also be reduced by the production of low-dusting formulations, by the observance of precautionary phrases, and by the use of suitable protective clothing.

Phthalate esters, cystic kidney disease in animals and possible effects on human health: a review.

1. Phthalate esters are known to cause hepatic peroxisome proliferation in rodents and, after prolonged administration, hepatocarcinogenesis. Peroxisome proliferators as a group are hepatocarcinogenic. The mechanism is not known but it does not appear to involve a direct genotoxic element. 2. DEHP and DBP have been shown to cause renal cysts in rodents and they also produce renal peroxisome proliferation. There are no data to causally link the two phenomena. 3. Although renal cysts have been noted in haemodialysis patients and haemodialysis is a route of exposure to DEHP, there are no data to suggest a cause and effect relationship. 4. More studies are needed on the mechanism of renal cystogenesis.

Strength of meaning--strong words and a certain message?

The ability to convey specific meanings is important to scientists in their writing. However, difficulties arise when the ideas to be portrayed are judgmental. While extreme terms expressing strength of meaning are readily understood, more subtle ones appear not to be.

Acetylhydrazine hepatotoxicity: the role of covalent binding.

Acetylhydrazine, a human metabolite of isoniazid and a hepatotoxin, binds covalently to rat liver protein and to the proteins of other organs in vivo. The covalent binding to macromolecules in the liver, but not to those of other organs, was increased by pretreatment with phenobarbital. The time course of binding to total hepatic protein and to hepatic subcellular fractions was also altered by phenobarbital pretreatment. There was a concommitant time-dependent decline in cytochrome P-450 levels in the phenobarbital pretreated animals, but not controls. Acetylhydrazine did not produce detectable lesions in organs other than the liver, despite the occurrence of covalent binding to protein in those organs. The results suggest that only a critical fraction of the covalent binding to specific subcellular components is related to the subsequent development of tissue lesions.