Applied Fish Pharmacology
AQUACULTURE Volume3 1. Fish Nutrition in Aquaculture Sena S. De Silva and Trevor A. Anderson ISBN 0-412-55030-X 2. Environmental Management for Aquaculture Alex Midlen and Theresa Redding ISBN 0-412-59500-1
Applied Fish Pharmacology K. M. Treves-Brown MA, Vet MB ( Cantab ), Master of Arts, Bachelor of Veterinary Medicine, Cambridge University MRCVS, Member of the Royal College ofveterinary Surgeons, London SPRINGER-SCIENCE+BUSINESS MEDIA, B.V.
Library of Congress Cataloging-in-Publication Data ISBN 978-90-481-4014-5 ISBN 978-94-017-0761-9 (ebook) DOI 10.1007/978-94-017-0761-9 Printed on acid-free paper Ali Rights Reserved 2000 Springer Science+Business Media Dordrecht Originally published by Kluwer Academic Publishers in 2000 N o part of the material protected by this copyright notice may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording or by any information storage and retrieval system, without written permission from the copyright owner.
SERIES EDITOR'S PREFACE Fish culture is a growing agribusiness. Considering the value of that business, the frequency and often devastating nature of fish diseases, it is perhaps surprising that a comprehensive text explaining the pharmacology of fish medicines has not been available until now. In the space of little over 300 pages, some 22 Chapters have been organised into four parts: General Considerations (3 Chapters); Antibacterial Drugs (8 Chapters); Other Chemotherapeutic Agents (4 Chapters) and Pharmacodynamic Agents (7 Chapters). Keith Treves-Brown is to be congratulated on producing a comprehensive yet readable text on a topic few have ventured to touch on to date. An explanation of the pharmacology of fish medicines is indeed long overdue and I feel sure that Keith Treves-Brown's book will be a source used by Fish Health Managers for many years to come. Indeed, I fully expect it to become a part of the essential reference collection on a great many fish farms. Veterinarians specialising in fish diseases will fmd it invaluable. Students studying fish diseases, whether as part of a general aquaculture course or as a specialist subject, will also wish to have access to it. Post-graduates will fmd it a constant source of much useful information, as I am sure will managers working in 'Regulatory Agencies'. While Keith Treves-Brown's experience and examples are naturally European, the topic of 'Applied Fish Pharmacology' has a universal appeal and this book should be of great value throughout the world of fish culture. As such it is a very welcome addition to the 'Aquaculture Book Series'. Michael G. Poxton Editor, Aquaculture Series
CONTENTS ACKNOWLEDGEMENTS xi PREFACE xiii PART ONE GENERAL CONSIDERATIONS CHAPTER 1 - Methods of Drug Administration 1 1.1 Water medication 1 1.2 In-feed medication 6 1.3 Gavage 12 1.4 Injection 12 1.5 Topical application 15 CHAPTER 2 - Safety of Fish Medicines 16 2.1 Aspects of safety 16 2.2 Safety to the target species 17 2.3 Safety to the operator 18 2.4 Safety to the consumer 19 2.5 Safety to the environment 22 CHAPTER 3 - The Law 26 3.1 The aims of legislation 26 3.2 Labelling 27 3.3 Drug usage outwith MA provisions 28 3.4 Legal control of in-feed medication 30 3.5 Environmental safety legislation 31 3.6 Consumer safety- Regulation 2377/90/EEC 34 3.7 Market authorizations 38 3.8 Future developments 50
viii PART TWO ANTIBACTERIAL DRUGS CHAPTER 4 - Comparative Aspects 55 4.1 Introduction 55 4.2 Selection of antibacterial drugs 56 4.3 Environmental safety 58 4.4 Bacterial resistance 61 CHAPTER 5 - Tetracyclines 64 5.1 Group characteristics 64 5.2 Uses of oxytetracycline 65 5.3 Pharmacokinetics of oxytetracycline 66 5.4 Pharmacodynamics of oxytetracycline 76 5.5 Oxytetracycline in the environment 79 5.6 Other tetracyclines 81 CHAPTER 6 - Penicillins 83 6.1 Group characteristics 83 6.2 Uses 83 6.3 Dose rates 84 6.4 Pharmacokinetics 85 CHAPTER 7 - Macrolides 87 7.1 Group characteristics 87 7.2 Pharmacokinetics.of erythromycin 87 7.3 Toxicology of erythromycin 90 7.4 Control of bacterial kidney disease 91 7.5 Other macrolides 94 CHAPTER 8 - Sulfonamides 95 8.1 Group characteristics 95 8.2 Pharmacokinetics 96 CHAPTER 9 - Potentiated sulfonamides 106 9.1 Group characteristics 106 9.2 Pharmacokinetics 112 CHAPTER 10 - Quinolones and Fluoroquinolones 117 10.1 Group characteristics 117 10.2 Nalidixic acid 119 10.3 Oxolinic acid 123 10.4 Pirornidic acid 130 10.5 Flumequine 131 10.6 Other ftuoroquinolones 137
ix CHAPTER 11 - Other Systemic Antibacterial Agents 11.1 Nitrofurans 11.2 Chloramphenicol 11.3 Florfenicol 143 143 148 151 PART THREE OTHER CHEMOTHERAPEUTIC AGENTS CHAPTER 12 - Systemic Anti-protozoal Agents 12.1 Fumagillin 12.2 Nitroimidazoles CHAPTER 13 - Externally applied antimicrobial agents 13.1 Formalin 13.2 Malachite green 13.3 Leteux-Meyer mixture 13.4 Chloramine-T 13.5 Copper sulfate CHAPTER 14 - Ectoparasiticides 14.1 Metazoan ectoparasites 14.2 Organo-phosphorus compounds 14.3 Hydrogen peroxide 14.4 Ivermectin 14.5 Cypermethrin 14.6 Benzyl-ureas CHAPTER 15 - Anthelmintics 15.1 Worm parasites of fish 15.2 Flukicides 15.3 Tapeworm and roundworm treatments 155 155 159 161 161 164 171 172 176 180 180 180 188 191 195 197 200 200 201 204 PART FOUR PHARMACODYNAMIC AGENTS CHAPTER 16 - Anaesthetics 16.1 General considerations 16.2 MS-222 16.3 Benzocaine 16.4 Other anaesthetic agents 16.5 Hypnotics and sedatives 206 206 209 211 214 217
X CHAPTER 17 - Breeding induction agents 220 17.1 Reproductive physiology 220 17.2 Drugs used in breeding induction 224 17.3 Procedures for individual species 230 CHAPTER 18 - Sex control 241 18.1 The objectives of sex control 241 18.2 Induction of triploidy 242 18.3 Medicinal production of all-female populations 243 18.4 Sex control in tilapia 246 18.5 Production of sterile carp 248 18.6 Induction of sex change in hermaphrodite species 249 18.7 Safety Aspects 249 CHAPTER 19 - Immuno-stimulants 251 19.1 Immuno-modulation 251 19.2 Glucans 254 19.3 Other immuno-stimulants 256 CHAPTER 20 - Vaccines 260 20.1 Evaluation 260 20.2 Routes of administration 266 20.3 Available vaccines 271 CHAPTER 21 - Osmoregulators 276 21.1 Physiological osmo-regulation 276 21.2 Medicinal osmo-regulation 277 CHAPTER 22 - Disinfectants 281 22.1 Uses of disinfectants 281 22.2 Chemical disinfectants 282 APPENDICES I Trade marks of products specifically formulated for use in fish 289 II Linnean and English names of cultured species of finfish 293 III Glossary 297 INDEX 299
ACKNOWLEDGEMENTS Advice on chapters on which they have particular expertise has been freely given to me by Dr. David Alderman of The Centre for Environment, Fisheries and Aquaculture Science (CEFAS) and Mr. Edward Branson, MRCVS. All the other chapters have been reviewed by my son, Dr. Bernard Treves-Brown, a chemist; and he has produced the chemical formulae which are the subject of several of my figures. My wife, Ruth, has produced computer print-outs of over 20 tables. I am grateful to them all for the time and attention they have given. Mrs. Sue Walker, librarian at CEFAS, has been unfailingly patient and helpful, not only during my many visits to her library but also on the innumerable occasions when I have telephoned and asked her to drop everything and look up an odd point in a journal for me.
PREFACE In writing a book with any technical content at all one has to decide what degree of prior knowledge the reader will bave. This book is intended to be of worldwide application, and it is hoped that it will prove of interest to numerous people in fish farm management and also some involved with other aspects of aquaculture such as the supply of ornamental fish. This means that the hoped-for readership will have wide variations in prior knowledge both qualitatively and quantitatively. As a veterinarian myself I have chosen as the person to whom to address the book a newly qualified veterinarian. I am assuming that he or she will be very well versed in the medicine of homoiotherms, but know very little about poikilothermic vertebrates despite their great, and increasing, importance as sources of protein for mankind. This means I am assuming considerable understanding of the different types of medicines used by veterinarians, but occasionally pointing out some aspects of fish behaviour and physiology, particularly osmo-regulation, which non-veterinarian readers may regard as elementary. Above all one must keep emphasizing the fundamental importance of temperature to the rate of biochemical, including pharmacological, processes. This book is about what is known, not what is legal. Readers who are aware of my previous employment in the Veterinary Medicines Directorate (V.M.D.), the UK government regulatory body, may be surprised at my advocating medicinal applications which are illegal in UK. Three points need to be made: first, I am not advocating but stating what has been reported; secondly, even though something is illegal in one or a few countries it is probably legal in many others, and thirdly, law is continually changing. In the last context it must be remarked that the European Union legislators have acknowledged that current medicines law is unsatisfactory in its application to fish; and significant changes have been made to the procedures for determining maximum residue limits in fish tissues during the time taken to write this book. Another group who may be surprised at my writing this book are the active fish pharmacologists. I am not one; in fact I am happy to admit that I have never done any laboratory or field research in my life. I have nevertheless spent most of my career studying veterinary pharmacological research reports and deciding what they prove in terms of justifiable claims and necessary warnings and precautions for veterinary medicinal products. I have done this in pharmaceutical industry, writing many labels and directionsfor-use leaflets which have been widely used and translated into many languages; I have done the same thing in V.M.D., and I have done the same thing again in writing this book. Many fish pharmacologists may notice their results quoted selectively and sometimes without acknowledgement. To address the second point first, the fact is that a majority of readers would not study research papers in the scientific literature even if the references were given. Those who read references are research workers who wish either to use the same techniques or to dispute the conclusions; this book is not primarily intended for them.
xiv The first word of the title is 'Applied' because I have aimed to cover those pharmacological data, and only those data, which can be used in the prevention and treatment of fish disease or the enhancement of fish productivity. Where I have listed research reports under 'Further Reading' I believe the reader can obtain additional information relevant to the aims of the book. In keeping with those aims I have tended to use units which modem scientific purists will regard as old-fashioned. My experience leads me to believe that to be easily read is more important than to be scientifically fashionable, and where dose rates are concerned clarity is paramount. To the veterinarian in practice and to the fish farmer I believe 'mg/kg/day' is preferable to 'mg.kg- 1.d- 1 ', and 'ppm' obviates problems of whether to use 'mg/kg' or 'J.Lg/g' (or should it be ' 1 6g 0 -. g - ~ Even '? ). scientists {both authors and reviewers) sometimes get confused by the modem notation: one paper listed in this book gives the units of the concentration of azamethiphos in water correctly as mg.l- 1 on three occasions and wrongly as 'mg- 1.L' on over 40 occasions! Another foreseeable criticism of this book is that it is patchy in its coverage of the subject- some aspects are covered extensively and some not at all. This is regrettably true; it reflects the available data. Two aspects of the research reports I have read have been disappointing to one with the particular interests I hold. I have read at times of elegant and pains-taking research which does not have any obvious application. How many studies have been made of elimination half-lives of residues of drugs in serum or plasma? We do not drink fish blood; we eat the musculature! How often do we read computer calculations to many significant figures of transference rates of drugs to deep or superficial compartments of a fish? The equations may give remarkable correlations with observed plasma concentrations but what the clinician needs to know is the identity of the tissues or organs represented by those compartments. A small volume of distribution is relevant, albeit negative, information for the clinician; a large volume of distribution says nothing - is the drug widely distributed at low concentration or is it selectively concentrated in one organ? The second disappointment is the narrow range of fish species and drugs on which research has been concentrated. The former is perhaps inevitable; well-equipped and well-staffed laboratories tend to be in places where salmonids or channel catfish are the predominant farmed species, although one must not overlook the important work the Japanese have done with the ayu and yellowtail. Nevertheless it is extraordinary how much has been published about oxytetracycline, a rather unsuitable antibiotic for in-feed administration to fish, and how little has been published about amoxycillin which seems to me to be far superior. There is much more literature about oxolinic acid than about flumequine, but it is the latter which now has an MRL assigned in the EU*. I hope this book will help veterinarians to prescribe wisely and fish farmers to administer drugs safely and effectively. Although I have written that the book is not primarily intended for research pharmacologists I hope it will help them to concentrate their attentions where they are most needed. *An MRL has recently been assigned to oxolinic acid.