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[Drugs in veterinary medicine. The role of the veterinary drug industry].

Veterinary medicines constitute an unescapable element in the scheme of animal health and welfare. Nowadays, they are used more and more to improve health and productivity in farm animals. When a veterinary medicine is prescribed it must not only be effective but must also be safe for both animals and humans. Due to ever changing regulations and constant improvements in residue detection techniques it is necessary to conduct new investigations with existing products. It therefore costs a great deal of time and money to introduce, and maintain, a product in the market. In future, therefore, fewer medicines with more limited indications will be introduced and these will be to combat important production disorders in the more significant species only. In view of the above, research and production will be restricted to large, international, concerns. Due to our well structured agricultural industry and the existence of well organized and equipped veterinary research institutions, and practitioners, Holland is able to play an important role in the development of veterinary medicines. Close co-operation between all involved parties coupled with an efficient registration procedure is not ony of benefit to the veterinary pharmaceutical industry but also for international recognition of our national animal husbandry industry, ancillary industries and veterinary and other consultants. In this scheme of things the accent is not upon qualifications but upon the skills of veterinarians - wherever placed - who are involved in the administration of veterinary medicines.

Animals

[Veterinary drugs and good veterinary practice].

The following definition of 'Good Veterinary Practice' in relation to pharmacotherapy is presented: 'The selective use (in accordance with directions for users) of veterinary drugs registered by the authorities in those indications in which they are permitted when the diagnosis has been established and in which the problem of residues in foods of animal origin on using these agents has been taken into account'. The following recommendations are made with reference to 'Good Principles of Veterinary Practice': (1) Current training and supplementary training in the fields of pharmacy and pharmacotherapy should be adjusted in the light of recent developments in society. (2) The development of simple, rapid and reliable tests for the detection of pathogenic agents and residues of veterinary drugs should stimulated. (3) The development of conveniently arranged and standardised data sheets in generally comprehensible terms should receive sufficient attention. (4) Quality control, particularly of generic products, deserves adequate attention. (5) The institution of a Side-Effects of Veterinary Drugs Office, in which the authorities, manufacturers and other parties concerned co-operate closely, is eminently desirable. (6) The establishment of a Veterinary Drugs Committee in which all interested parties are represented, is of the utmost importance within the framework of recommendations on policy to the authorities.

Animals

[Veterinary drugs, the veterinarian and the Veterinary Drug Act].

A number of features of the Veterinary Medicinal Products Act, which are of importance to veterinarians, are reviewed. These features result in a number of consequences connected with obtaining and handling veterinary drugs. These consequences are discussed.

Animals

[The Veterinary Drug Act and rational pharmacotherapy. Various marginal notes on the registration and channeling of veterinary drugs].

A short introductory note is followed by a more detailed discussion of a number of aspects of the administration of the Veterinary Medicinal Products Act. Among other things, attention is paid to the following subjects: the Registration of Veterinary Drugs Committee (RVDC) and its working parties (no participation of specialists from the Faculty of Veterinary Medicine, no varied membership of the Veterinary Drugs Committee), the veterinary use of drugs registered for human use (supplementary registration), the position of particular species of animals (supplementary registration), the records (no environmental requirements, absence of clear directions for the toxicological evaluation of veterinary-drug metabolites, risks of the number of veterinary drugs available being reduced) and the criteria of directing veterinary drugs into specific channels ('veterinarians only' system, role of pharmaceutical chemists). It would also appear to be advisable that the Committee specify within a short time which antibiotics are not eligible for veterinary use. This also holds good for substances such as mutagenic and carcinogenic compounds showing doubtful toxicological characteristics.

Animals

[Toxicological considerations in the evaluation of veterinary drugs].

Interactions between veterinary pharmacotherapy, toxicology of residues, prevention of residues of veterinary drugs and the evaluation of veterinary drug files are discussed on the basis of a number of examples. Sulphadimidine is used to treat atrophic rhinitis in medicated feeds which do not benefit the animal but are the cause of persistent sulphonamide residues in feed mills and husbandry. Carbadox is a potentially effective prophylactic feed additive for the prevention of swine dysentery, but is mostly used in high dosages which are almost toxic for the animals, and used during unnecessary prolonged periods. It is also prescribed as a therapeutic agent in which case a symptom of poisoning, dry faeces, is mistaken for a sign of recovery. Carbadox and/or its metabolites are carcinogenic and its use should be restricted to a bare minimum. Furazolidone is an example of an effective veterinary drug, the use of which should be limited by the fact that detoxification mechanisms of the animals, may result in the appearance of reactive metabolites which are available in the gastro-intestinal tract of the consumer. The central issue in a 'minimal residue' policy regarding the use of veterinary drugs should be the selection of effective drugs. Such a selection could result in a significant reduction of the incidence of veterinary drug residues. Second to this issue is the question of the extent to which residue toxicology should modulate the use of veterinary drugs.

Animals

[The Veterinary Drug Act, the Veterinary Practice Act and the cattle farmer].

The concept of 'local practising' will disappear in the new legislation. This will render veterinary medicine by mail order possible. From the point of view of the quality of the ultimate product, this development should be strongly rejected. The section will benefit by an expert and payable herd management programme which has as its object a justified use of drugs and a 'clean ultimate product' (healthy animals).

Animal Husbandry

[Records and the use of veterinary drugs].

The new Veterinary Drugs Act is in process of development. The final form which this law will take on will probably be clearer by the time of the 1983 annual congress. It can be expected that only registered drugs will then be permissible for use in treatment. A drug is registered when records are provided and found to be adequate, which show that the drug is effective and does not have any injurious side-effects or results in the appearance of residues after normal use. Drawing up a record of this type requires thorough investigation of the drug, in which experimental studies in animals play an important role. The problem of residues does not enter into the matter in the case of veterinary drugs used in companion animals, though beyond this the registration system will not differ markedly from that of other agents. This means that drugs used in human medicine as such are not permissible for use in companion animals. As several of the required data from the records of these drugs will then be available, composing a complete record will not cause any insurmountable problems. The situation is more complicated in the case of homeopathic and allied therapeutic agents.

Animals

Dietary intake estimates as a means to the harmonization of maximum residue levels for veterinary drugs. II. Proposed application to the Free Trade Agreement between the United States and Canada.

The Free Trade Agreement between the United States and Canada (FTA) went into effect January 1, 1989. To implement certain provisions of the agreement on technical regulations and standards, the United States Food and Drug Administration's Center for Veterinary Medicine, Health and Welfare Canada's Bureau of Veterinary Drugs, and Agriculture Canada established the Working Group on Veterinary Drug Tolerances. The progress of the working group and its continuing efforts to harmonize tolerances for approximately 15 veterinary drugs are discussed. This paper proposes use of the toxicologically determined acceptable daily intake (ADI) for the drug as the safety standard for reaching conclusions on the acceptability of residues in meat for human consumption. Specifically, the "equivalence" of different MRLs for the same veterinary drug would be determined by considering whether they are likely to result in dietary residues that exceed the other country's ADI for the drug. Estimates are made for the veterinary drugs lasalocid, fenbendazole, morantel tartrate, halofuginone, and tilmicosin. Based on these estimates, the U.S. and Canadian MRLs for each drug would be considered equivalent for trade purposes.

Animals

Codex committee on veterinary drug residues.

There has been widespread international concern over residues of veterinary drugs in food. However, until recently, there was little international cooperation in trying to find solutions to the problem. Many nations have taken steps to control the increased use of veterinary drugs, but the rules governing their use vary widely from country to country. Sharing of scientific expertise and other resources between countries would markedly improve this situation. With the need for international cooperation mounting, concerned drug regulators from 20 countries met in 1982 and again in 1984 to discuss international use of veterinary drugs. The group repeatedly called for a Codex committee on veterinary drug residues. At its 1983 meeting in Rome the Codex Alimentarius Commission convened an Expert Consultation to consider the need for a new committee. That international group of experts strongly agreed that a standing committee under the sponsorship of the commission should be established. In July of 1985, the commission unanimously voted to establish a new Committee on Residues of Veterinary Drugs in Food. The United States was chosen as host country. The committee will work closely with several existing Codex committees, but it has a clear mandate of its own. Its responsibilities will include establishing a list of priority drugs for review, recommending maximum residue levels, developing codes of practice, and reviewing analytical methods used to control veterinary drug residues. This fall, a new Codex committee has met for the first time--the Codex Committee on Residues of Veterinary Drugs in Food.(ABSTRACT TRUNCATED AT 250 WORDS)

Agriculture

[Veterinary Drug Act].

The Dutch Veterinary Drug Act is reviewed and the consequences of a number of aspects of this act are discussed.

Animals

[The use of pharmacological criteria in the toxicological evaluation of veterinary drugs].

The toxicological evaluation of residues of veterinary drugs in foods of animal origin, which is done within the framework of the Netherlands Veterinary Drugs Act, is based on an EEC guide line in which, in addition to the clinical and analytical criteria, the requirements regarding the pharmacological and toxicological evaluation are laid down. In principle, this evaluation is based on classical toxicological criteria. As veterinary drugs have a specific pharmacological action, it is essential that these pharmacological effects should be in included in the toxicological evaluation in view of an adequate protection of public health. The selected starting point is that a pharmacological effect desired in a target animal is regarded as an undesirable effect in consumers. In this presentation, two examples are referred to, viz. the bèta agonist clenbuterol and the bèta-blocking agent carazolol; the approach is compared with a 'classical' toxicological evaluation. This shows that the acceptable daily intake in human individuals (ADI), based on pharmacological criteria is lower by a factor of approximately 50 than is the ADI on the basis of 'classical' toxicological criteria. This clearly illustrates the value of this approach in protecting the health of consumers.

Adrenergic beta-Antagonists

[Current regulations controlling veterinary drugs].

The quality, effectiveness, and innocuousness of veterinary drugs are evaluated with regard to farm animals and in relation to the harmlessness of animal products for humans. That is why supervision functions during production, registration, delivery, and application of veterinary preparations to animals impose higher requirements and acquire special importance on a national and international scale. Beside the pharmaceutic control on definite occasions supervision includes preclinical and clinico-pharmacological studies as well as permanent post-registration surveillance. Checks are not uncommon along with toxicologic pharmacokinetic, and residual amount studies and studies concerning quarantine dates, employing highly sensitive, less labour-consuming, short-time, and cheaper methods worked out and perfected at the control Institutes. In this connection the work of such Institutes is not only associated with supervision but also with scientific research. Control activities include also the check of information on veterinary drugs and the pollution control in the production and use of these drugs. Control Institutes should control in the production and use of these drugs. Control Institutes should also take care of training cadres. Due to the intense commercial activity with veterinary drugs and products of animal origin between different countries it is necessary to intensify also the international collaboration between control Institutes and laboratories.

Academies and Institutes

Some considerations on veterinary drug use and supply in Nigeria.

There is widespread misuse of veterinary drugs in Nigeria resulting from controlled and unsupervised drug administration, underdosing and incomplete treatment. Development of resistance and toxicity are common consequences of this misuse. Drug shortage, uneven distribution, preponderance of fake and/or expired drugs and inadequate local drug production are some of the problems identified in veterinary drug supply. All these problems have an adverse effect on animal health and productivity and are related to an improperly coordinated veterinary service and the non-existence of national veterinary drug policy. Suggested solutions include rehabilitation and restructuring of the veterinary service, improved funding to support drug purchase, installation of self-servicing revolving funds, partial privatization, drug manufacture and appropriate legislations for veterinary drugs. These proposals are expected to overcome bottlenecks encountered in drug supply, distribution, delivery, prescription and use. Projections and plans must also be made toward the local development and manufacture of drugs for animal disease.

Animal Husbandry

[Marginal notes on the admissibility and the application of veterinary drugs and animal feed additives].

In principle, registration of a veterinary drug requires more detailed testing for toxicity than does a human drug; among other things, because of possible presence of drug residues in the edible tissues of animals. It is stated that this is not necessarily a requirement for all veterinary drugs. It is essential, however, when a drug is used for mass-medication. Three objectives may be differentiated in these cases, namely, a nutritional a preventive and a curative purpose. In discussing these objectives, it is pointed out that (despite the fact a Veterinary Drugs Act has not been adopted so far) the authorities have made the necessary arrangements to ensure the desired effectiveness and innocuity both in the target animal and in the consumer. When specially medicated feed as well as medicated drinking water are used, the situation becomes more difficult. When veterinary drug residues are being toxicologically evaluated, however, more attention should be paid to pathological studies in target animals. Establishing a veterinary toxicological data bank is advocated.

Animal Feed

[Scientific basis in the setting of residue limits for veterinary drugs in food of animal origin taking into account the presence of their metabolites].

Maximum residue level (MRL) for veterinary drugs in food of animal origin has been proposed by FAO/WHO, as a new evaluation procedure taking into account the presence of metabolites for the regulation of veterinary drug residues. The MRL is the maximum concentration of residue resulting from the use of a veterinary drug that is recommended to be legally permitted as acceptable in a food. It is established from the Acceptable Daily Intake (ADI) obtained from the data of toxicological studies, the residue concentration of the drug when used according to good practice in the use of veterinary drugs, and the lowest level consistent with the practical analytical methods available for routine residue analysis. Among the veterinary drugs, some chemicals contain a large amount of bound residues that are neither extractable from tissues by the analytical method identical with that used in parent chemicals. Especially, the bioavailable residues which are probably absorbed when the food is ingested are of great toxicological concern. In this case, the FAO/WHO recommends that the MRL can be established after the calculation of daily intake of residues of toxicological concern by the addition of both the extractable and bioavailable bound residues.

Animals

Investigation of dissociation enhanced lanthanide fluoroimmunoassay as an alternative screening test for veterinary drug residues.

Both the number of drugs used in veterinary medicine and the diversity of procedures employed to detect their residues are ever increasing. Many laboratories that carry out such testing have employed a variety of immunoassays to serve as rapid screening tests. Owing to the high sensitivity, good reproducibility and availability of multi-analyte assays dissociation enhanced time-resolved fluorescence immunoassay (dissociation enhanced lanthanide fluoroimmunoassay, DELFIA) kits have become a market leader in the human clinical field. No commercial DELFIA kits are presently available for veterinary drug analysis. A DELFIA method was developed for the quantitative analysis of residues of medroxyprogesterone (MP) in bovine bile. Commercially available DELFIA reagents were used in a microtitre assay format. Within- and between-assay sr values (relative standard deviation) were 4.2-9.9 and 5.1-8.5%, respectively. Detection limits were calculated (mean + 3 s of a known negative population) as being 0.52 and 4.91 micrograms l-1 for male and female animals, respectively. A second study was carried out to optimize the labelling of haptens with a range of lanthanide metals. Purification of the hapten-lanthanide conjugates produced was achieved using fast protein liquid chromatography. Sensitive standard curves were produced for nortestosterone and diethylstilbestrol (curve mid-points of 30 and 40 pg, respectively). By using two different lanthanide labels (Eu and Tb) the simultaneous measurement of these compounds in a single assay system was achieved. Use of a third lanthanide label (Sm) yielded a product of low signal intensity and sensitivity.

Anabolic Agents

Dietary intake estimates as a means to the harmonization of maximum residue levels for veterinary drugs. I. Concept.

The harmonization of standards and procedures for establishing tolerances or maximum residue levels (MRLs) for veterinary drug residues in edible animal products is a major goal of the international veterinary drug community. Such harmonization would contribute to easing trade barriers. This paper proposes use of the toxicologically determined acceptable daily intake (ADI) for the drug as the safety standard for reaching conclusions on the acceptability of residues in meat for human consumption. Specifically, the 'equivalence' of different MRLs for the same veterinary drug would be determined by considering whether they are likely to result in dietary residues that exceed another country's ADI for the drug. Two methods of estimating dietary intake are described, and estimates are made for the veterinary drugs albendazole and ivermectin. Based on these estimates, the US and JECFA MRLs for each drug would be considered 'equivalent' for trade purposes.

Albendazole

[Veterinary drug residues in food].

When veterinary drug residues are constantly present in sufficient amounts, they may give rise to toxicological, clinical and allergenic effects, and resistance may occur. Dreaded effects are those which are carcinogenic and allergenic in character, and the appearance of resistance. Antibiotics and 'bacterial' chemotherapeutic agents constitute the most important group as regards these effects.

Animals