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J. Vet. Pharmacol. Therap. 36, 105--115. doi: 10.1111/jvp.12041.

REVIEW ARTICLE

Veterinary pharmacology: history, current status and future prospects1

P. LEES* Lees, P., Fink-Gremmels, J., Toutain, P. L. Veterinary pharmacology: history,


J. FINK-GREMMELS & † current status and future prospects. J. vet. Pharmacol. Therap. 36, 105–115.
P. L. TOUTAIN ‡ Veterinary therapeutics, based on the art of Materia Medica, has been
practised for countless centuries, but the science of veterinary pharmacology
*The Royal Veterinary College, Hawkshead
is of very recent origin. This review traces the contribution of Materia
Campus, Hatfield, Herts, UK; †Faculty of
Veterinary Medicine, Veterinary Pharmaco- Medica to veterinary therapeutics from the Egyptian period through to the
logy, Pharmacotherapy and Toxicology, Utr- Age of Enlightenment. The first tentative steps in the development of the
echt University, Utrecht, Holland; ‡Ecole science of veterinary pharmacology were taken in the 18th century, but it
Nationale Veterinaire de Toulouse, Toulouse, was not until the mid 20th century that the science replaced the art of
France Materia Medica. This review traces the 20th century developments in
veterinary pharmacology, with emphasis on the explosion of knowledge in
the 35 year period to 2010. The range of factors which have influenced the
current status of the discipline are reviewed. Future developments are
considered from the perspectives of what might be regarded as desirable and
those innovations that might be anticipated. We end with words of
encouragement for young colleagues intent upon pursuing a career in
veterinary pharmacology.
(Paper received 17 January 2013; accepted for publication 17 January 2013)
Peter Lees, D Sc, The Royal Veterinary College, Hawkshead Campus, Hatfield,
Herts., AL9 7TA, UK. E-mail: plees@rvc.ac.uk

INTRODUCTION
THE DOMINANCE OF THERAPEUTICS BY MATERIA
MEDICA
This manuscript is dedicated to those many colleagues from
previous generations, who laid the foundations of veterinary
We should remind ourselves that, based on the art/science of
pharmacology and toxicology, the twin disciplines served by
Materia Medica, veterinary therapeutics is an old discipline,
EAVPT, ECVPT, AAVPT and ACVCP. The manuscript is direc-
whereas the discipline of veterinary pharmacology is a new
ted especially to those young colleagues in many countries
science - <100 years old; indeed, it has emerged and devel-
who will carry forward these disciplines, notably those ECVPT
oped almost entirely in our working lifetimes, that is to say
Residents, who have recently achieved or who aspire to mem-
post 1960. When in 1968 Frank Alexander, a pioneer of vet-
bership of the European College. We trust that they, like their
erinary pharmacology, was elected to a personal chair in vet-
forbears, will devote their working lives to the pursuit of
erinary pharmacology at Edinburgh University, he delivered
excellence in our disciplines, as teachers, researchers and regu-
an inaugural lecture entitled: ‘Materia Medica to veterinary
lators in academia, industry or regulatory affairs. Between
pharmacology: a transition’ (Alexander, 1969) to explain why
them, the three co-authors of this lecture have devoted
and how the teaching of Materia Medica that persisted up to
upwards of 130 years of effort to this cause, which therefore
1952 at the ‘Dick vet’ school was replaced by veterinary phar-
clearly implies that the baton must soon be passed on to our
macology, a discipline having its own legitimacy. At least
younger colleagues. We encourage our successors to note
97%, perhaps 99%, of drugs currently licensed for veterinary
that the intellectual rewards of a career in veterinary phar-
use have been introduced in the last 50–60 years. This has
macology and toxicology are there for the taking. As the
been a monumental achievement (transforming animal health
early English chemist Humphrey Davey remarked, ‘there has
and welfare for the better), to which individuals in academia
never been a higher source of satisfaction than the pursuit of
and regulatory affairs have made major contributions. How-
science’.
ever, most of all, it stands to the credit of colleagues in the
pharmaceutical industry – they have made this transformation
possible.
1 Over at least 30 centuries prior to the 19th century, human
Presented by Peter Lees as a plenary lecture during the 12th
International Congress of the European Association for and animal diseases were treated with a range of botanical,
Veterinary Pharmacology and Toxicology, held in mineral and other natural substances, described (often in great
Noordwijkerhout, The Netherlands, 8–12th of July, 2012. detail) in various Materia Medica texts. These have been dis-

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106 P. Lees et al.

cussed in several excellent 20th century reviews (Alexander, necessarily obtained from animal studies. By modern stan-
1969; Davis, 1984; Van Miert, 2000; Appelgren, 2009; Cun- dards, these were often barbaric, being conducted in the
ningham et al., 2010). The latter author has traced these early absence of anaesthetics. Nevertheless, in the early 19th
beginnings through the Egyptian, Greek, Latin and European century, the French physiologists/pharmacologists Magendie
medieval periods, to the Age of Enlightenment and on into the and Pelletier introduced a new period of drug discovery by
19th and 20th centuries. In the Egyptian period, the plants experimentation, injecting plant extracts of Papaver somniferum
used therapeutically were described in various papyri, the con- (containing opium alkaloids) and Nux vomica (containing
tents of which became known with the translation of the strychnine) intravenously. Magendie further showed that
Rosetta stone in 1822. The Ebers papyrus (1150 B.C.) covering drugs can be absorbed into the circulation after oral dosing to
15 prior centuries contained more than 800 prescriptions for exert systemic effects. From these investigations, Magendie
plasters, pills, suppositories and other dosage forms for specific and Pelletier developed a formulary prescribing dosages for
conditions. In India, Buddha not only prohibited the vivisec- administration to animals. In the mid-19th century, Claude
tion of animals, but established animal hospitals throughout Bernard, a student of Magendie, commenced the process of
the country. Later, Arrian, a Greek historian, described the extraction of active principles from plants, such as the skeletal
conditions and medications in such animal hospitals (Pinjra- muscle relaxant, d-tubocurarine from curare, previously
poles) at the time of the invasion of Alexander the Great. The known as a South American arrow poison. He demonstrated
Greek period, however, was dominated by the writings of its action in paralysing skeletal muscle without affecting CNS
Hippocrates (430 BC) and later those of Galen (94 AD). The functions.
former used extracts of the bark of the willow tree to ease the Through the work of these and other early pioneers, the
pain of childbirth. Interest in Salix alba revived in 1792 when science of pharmacology was starting to emerge in the early-
an English clergyman, Edward Stone, described its antipyretic mid 19th century. By mid century, further advances were
properties. However, domination of the views of Hippocrates facilitated by the rapid progress achieved in methods for
and Galen persisted for some 1400 years up to the Age of extracting and purifying drugs from plants, combined with
Enlightenment. advances in analytical and synthetic organic chemistries.
In the early 16th century, the Swiss physician, Paracelsus, These led, for example, to the recognition of the glycoside sali-
introduced into human medicine laudanum (opium) and a genin as the active principle in the bark and leaves of the wil-
range of extracts of various plants. He has achieved everlast- low. By 1875, there followed the introduction of first sodium
ing fame through his dictum that ‘all substances are poisons; salicylate, then phenacetin and then aspirin, as first genera-
there is none which is not a poison. The proper dose sets a tion analgesic/nonsteroidal anti-inflammatory drugs. However,
poison from a remedy’. As Appelgren (2009) points out, con- the sequence of events leading to the introduction of aspirin
cern was expressed at this time, relating to the use of plant in 1895 commenced several centuries BC, with use of the
extracts therapeutically in animals on the basis of human willow bark and leaves by Hippocrates followed by a descrip-
experience. The great Swedish botanist and doctor Carolus tion of its properties in the first century AD by Dioscorides in
Linnaeus voiced this concern, in stating: ‘human medicines the first true pharmacopoeia. The antipyretic properties of the
are used for animals without knowledge if they work, which willow were rediscovered in the 17th century by the Reverend
is devastating barbarism’ - a prescient thought for those of us Edward Stone of Chipping Norton, UK. There was, however,
interested in the 21st century in refining dosage schedules to only limited veterinary therapeutic use of aspirin prior to
optimize efficacy and minimize side effects through the appli- 1972. In this year, Lloyd Davis and colleagues published what
cation of pharmacodynamic (PD) and pharmacokinetic (PK) was perhaps the most game changing publication in veteri-
principles and data. nary pharmacology to that date (and even now) on ‘species
differences in transformation and excretion of salicylate’. Davis
and Westfall (1972) reported on salicylate half-life values in
EARLY DEVELOPMENTS IN PHARMACOLOGY the goat (0.8 h), horse (1 h), pig (5.9 h), dog (8.6 h) and cat
INCLUDING VETERINARY ASPECTS (37.6 h). They thus revealed the utter futility of extrapolating
dose regimens from one species to another, a common prac-
The 16th and 17th centuries marked the beginning of the tice prior to that time. PK differences were and remain the
experimental paradigm in biology and medicine, including cornerstone of veterinary pharmacology, but pre-1970, they
early pharmacological studies. Jesuit priests brought to Europe were largely unknown; this was principally due to the
the bark of the Cinchona tree from South America and applied unavailability of analytical techniques for establishing plasma
its antipyretic properties as the first antimalarial drug. In concentration–time relationships, with the exception of a few
1656, Sir Christopher Wren observed the effects of intravenous drugs of low potency, such as salicylate and drugs of the
opium in the dog, and in 1783, William Withering described sulphonamide group.
the use of extracts of foxglove in patients with congestive heart Three other great achievements in chemical and biological
failure. sciences had been made by the mid-late 19th and early 20th
Many of the experiments conducted, and therefore, much of centuries. First, an increasing understanding of the chemistry
the data generated from the early 19th century on were and physiology of the body led to the emergence of biochemis-

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Veterinary pharmacology 107

try and to recognition that hormones and neurotransmitters cine, and Folke Rasmussen in conducting classical studies on
interact either with enzymes or ‘receptive sites’ on cell mem- sulphonamide PK in farm animal species. Meanwhile, although
branes or intracellular organelles to trigger chain reactions penicillin had been discovered by Fleming in 1929, it was not
leading to physiological responses. From this knowledge, it was the Scot but a multidisciplinary team led by the Australian Flo-
only a short step to recognize that both older and new drugs rey who recognized its potential, thus opening up the new era
were acting on these same sites to elicit their responses, both of antibiotics for human and animal use. The first penicillin
beneficial and harmful. Secondly, the researches of Charles administration in man was in 1941, and a few years later,
Darwin led first to slow and then widespread acceptance that when penicillin was produced on an industrial scale, Doll and
evolution of all biological forms occurred through a process of Dimock reported on the blood concentrations of penicillin in
natural selection, the so-called survival of the fittest hypothesis. horses (Doll & Dimock, 1946). Shortly thereafter, Doll and
This simple concept laid the foundations for all biological sci- Wallace (1948) described the serum concentration profile of
ences and emphasized the basis for animal species, breed and streptomycin in the horse.
gender similarities and differences. Darwin further used an The ‘modern area’ of veterinary antimicrobial therapy was
astonishing range of drugs and chemicals in his detailed stud- initiated with the regulatory approval of the first veterinary flu-
ies on insectivorous plants. In the 20th and 21st centuries, the oroquinolone (enrofloxacin) in 1987, and the first third-gener-
most exciting advances, based on Darwinian concepts, relate to ation cephalosporin (ceftiofur) in 1988. These two classes of
the sciences of pharmacogenetics and pharmacogenomics; their antimicrobial drugs are currently the most challenged in terms
veterinary applications are destined to transform veterinary of public health, emphasizing that veterinary medicine needs
therapeutics in the medium-term future. Thirdly, the discover- urgently to review its antimicrobial drug armentarium, to meet
ies of Louis Pasteur on several fronts were truly monumental. public health expectations in the 21st century. Thus, there is
For the purposes of this review, we cite two of these: (i) the now a need to develop new compounds having minimal impact
discovery of bacteria and recognition of their supremely impor- on gut flora and on environmental bacterial ecosystems. These
tant role in the causation of infectious diseases, and (ii) his requirements might be met either by developing new anti-
work on chirality, recognizing the right- and left-handedness of microbial drugs or new local formulations of already available
the salts of lactic acid and further recognizing that the differ- drugs to guarantee an appropriate PK profile and/or PD selec-
ences between isomers extend from the crystal structure level tivity for target pathogens. This challenge for industry is not
to the molecular level. The latter discovery carries great impli- unattainable. In this regard, we recall that florfenicol was
cations for the now widely recognized PD and PK differences approved for food animal use in 1991 as an alternative to chl-
between enantiomeric drug pairs. oramphenicol, which was banned for food safety reasons.
During the first four to five decades of the 20th century, By 1960, drugs had become available, which could, at that
pharmacology emerged as a new discipline, but the scale and time, be described as ‘modern’. Some of these had been used in
application to therapeutics were limited. In the first decade, previous decades and centuries, in the form of plant extracts or
Paul Ehrlich, the father of chemotherapy, introduced the con- were present in the environment, notably in soil-dwelling
cept of selective toxicity of drugs against microbial cells, with micro-organisms. Others were simple chemicals produced syn-
relative safety for mammalian cells, through the selective thetically. They included digitalis glycosides, phenothiazine,
uptake of dyes such as Trypan Red. His work led directly to atropine, d-tubocurarine, morphine, halothane, aspirin, thi-
the introduction of the organo-arsenical group of synthetic opentone, the sulphonamides, benzylpenicillin, streptomycin
chemotherapeutics. Arsphenamine became available in 1910 and oxytetracycline. There were others of more dubious prove-
as the first anti-syphilitic drug. nance, including the flukicide and hepatotoxin carbon tetra-
In 1935, Gerhard Domagk introduced the first systemically chloride, which killed the flukes and sometimes the sheep as
effective and safe antimicrobial drug, Prontosil rubrum. It was well. Another memorable, if dubious, drug combination, com-
quickly realized that this dye was converted in vivo into the prising chloral hydrate, pentobarbitone and magnesium
active form, sulphanilamide. By chemical substitutions in the sulphate, was guaranteed to anaesthetize any horse when
sulphonamido grouping, there emerged the sulphonamide given intravenously.
group of broad-spectrum antibacterial drugs. The PD properties The case of digitalis glycosides further illustrates major pro-
of sulphanilamide were first reported in ruminants in 1939 by gress in clinical veterinary pharmacology and toxicology; in
Stableforth (1939), and the first articles on the veterinary PK the early 20th century, a major advance in human medicine
were then published on this drug class. Maclay and Slavin was the development of accurate radioimmunoassay methods
(1947) reported the excretion profile in dairy cows of several for determining serum concentrations of digitalis glycosides.
sulphonamides. This enabled drug monitoring in treated patients and the corre-
Several sulphonamides were specially developed for use in lation between concentration and therapeutic and toxic effects
veterinary therapeutics, after being modified by our colleague (as we would now describe it as a PK/PD relationship). Deitwe-
Franco Faustini (Italy), who was moreover one of the founding iler (1977) reported that therapeutic serum concentrations of
fathers of EAVPT. He held many patents on veterinary sulph- digoxin should not exceed 2.5 ng/mL in dogs.
onamides. We also note the pioneering work of Clarence Another major landmark was development of the avermec-
Stowe, in introducing sulphonamides into farm animal medi- tins. This derived from the isolation in Japan of a soil-dwelling

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108 P. Lees et al.

bacterium (S. avermitilis) and its evaluation in 1974 in the The development of more companion animal products, at
laboratories of Merck & Co., Inc. At Merck, this organism was the expense of therapeutics for farm animals, has been dri-
shown to produce potent anthelmintic substances, leading to ven, in part, by financial imperatives. The antiparasitic mar-
the introduction of ivermectin commercially in 1981, as the ket for dogs and cats has grown to a value of several billion
first endectocide for use in livestock. Subsequently, ivermectin dollars, driven by the development of highly efficacious agents
was introduced into human medicine for the treatment of for treating ectoparasites, with the introduction of fipronil
onchocerciasis (River Blindness). Ivermectin offers a unique (1994) and imidacloprid (1996), as discussed by Woods and
example of a veterinary drug subsequently developed for Knauer (2010). Currently, fipronil is the leading drug in
human medicine, as recently reviewed by Campbell (2012). respect of veterinary sales. The global extension of the
The contribution of veterinary pharmacology to human medi- human–animal bond has further favoured the companion ani-
cine is another facet of our discipline, although most veterinary mal therapeutics market. An additional driving factor, in the
drugs derive from either the human pharmaceutical industry new ascendancy of companion animal medicines, has been
(antibiotics, functional drugs) or the agrochemical industry the similarities between dogs and cats and humans, both
(insecticides, parasiticides, etc.). Our contributions derive pri- physiologically and in disease states, such as the arthritides
marily from animal research studies and from innovative prac- and cancers. Angiotensin-converting enzyme Inhibitors, such
tices. As examples, in the 19th century, veterinarians as benazepril, enalapril and ramipril, are now extensively
developed the first syringes, administered the first parenteral used for treating heart and kidney diseases in both canines
medications, introduced the technique of spinal anaesthesia and felines. Relative to the time courses of development in
and reported that diseases can be transmitted by arthropods, humans, animal diseases are often accelerated. Hence, their
as discussed by Quimby (1998). study over relatively short time scales assists advances in
understanding human disease mechanisms. This facilitates the
development of new products for both human and non-
FACTORS DETERMINING OR INFLUENCING PAST, human animals. This synergy is further promoted by major
PRESENT AND FUTURE DEVELOPMENTS recent advances in our understanding of the molecular basis
of disease processes and drug actions.
As well as advances in biological and chemical sciences, the Also significant for future advances in therapeutics is the
emergence and continuing development of veterinary impact of economic factors on medicine in general and
pharmacology has depended on changes in the structures and veterinary pharmacology in particular. At the present time, the
attitudes of global societies (Zengler and Palsson, 2012). In the elephant in the European room is the Great Recession. Its full
20th century, transportation and wars were transformed by the consequences and duration remain unknown at this time.
replacement of horses by automobiles and tanks. However, with However, advances in veterinary therapeutics are necessarily
increasing affluence, equine activities relating to competitive driven by commercial considerations. If the market declines
sports and leisure activities have guaranteed a continuing role and/or if development and registration costs increase, innova-
for the horse in society. Dogs retain only a minor role as working tions may stall or even cease. Without a fair profit, there can
animals but now, with cats and other species, have both diversi- be few if any new products. Nevertheless, societal demands for
fied and expanded their role as pets. Dogs and cats in particular improvement in animal health and welfare programmes will
are now widely accepted as integral family members. For food- stimulate research into existing and new clinical circumstances
producing species, the introduction of novel anthelmintics and and conditions, requiring pharmacological intervention.
antimicrobial drugs to control and prevent infectious diseases As well as food safety considerations, arising from drug, drug
has combined with changes in husbandry practices to provide a metabolite and pesticide residues in foodstuffs (Reeves, 2010;
greatly expanded availability and affordability of meat and dairy Lees & Toutain, 2012), advanced and developing societies are
products, first in industrialized and more recently in developing increasingly concerned with the impact of veterinary medicines
countries. At the same time, societies now place major and on the environment (Boxall, 2010). Environmental conse-
sometimes unrealistic demands on ensuring the safety and effi- quences of treating cattle with ivermectin relate to the effects
cacy of drugs used in animals, as well as the safety of foodstuffs of excreted drug on the cow pat fauna, associated with the
derived from food-producing species. These demands add consid- absence of dung-degrading insects (Wall & Strong, 1987). This
erably to development and marketing costs; the danger for the discovery was very influential in directing focus on the envi-
future is that they could act as a brake on new product develop- ronmental impact assessment for veterinary medicinal prod-
ment. Safety demands can also lead to the banning of drugs that ucts, leading to the release of VICH harmonized guidance in
were formerly used for decades in veterinary medicine and are 2000. Also of great concern is the transfer of antimicrobial
still in use in human medicine. An example is metronidazole resistance factors (zoonotic pathogens or genes of resistance)
(Flagyl©), an antiprotozoal and antibacterial agent that was between species, including the theoretical and much hyped risk
shown to be genotoxic and possibly carcinogenic in man. The of possible inability to treat life-threatening human as well as
ban on this drug left the poultry industry without an effective animal diseases, arising from the use of antimicrobial drugs in
treatment for histomoniasis and the disease re-emerged with up animals. For a scientifically based review of this topic, see Mar-
to 100% mortality in turkey flocks. tinez and Silley (2010).

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Veterinary pharmacology 109

All of the foregoing factors have led to extensive consider- ‘drugs’, with the subclasses ‘pharmacology’ and ‘veterinary sci-
ation of the desirability of establishing global harmonization of ences’ (and veterinary drug articles as a percentage of pharma-
regulatory policies and guidelines to govern the licensing of cology articles) together with numbers of veterinary citations,
veterinary drugs. Progress here is urgently needed. This is average veterinary citations per articles and the H-index (for
especially true for antimicrobial drugs. According to Shryock definition see below). There was a more than tenfold increase
(2004), the discovery, development and marketing of anti- in the number of ‘veterinary science’ article from 219 in 1975
infective products are at an important cross-roads. The current –1979 to 2506 in 2007–2010. Corresponding figures for
uncertainties regarding the regulatory acceptance of new anti- ‘pharmacology (nonveterinary)’ articles were 4833 in 1975–
microbial drugs have led to a very regrettable reorientation of 1979 and 54 292 in 2007–2010. The number of veterinary
research, away from traditional antimicrobial drugs and science (drug) articles has been within the range 4.53–6.23,
towards other products, having an increased probability of as a percentage of articles in pharmacology during the whole
acceptance in the market place and with better financial period. There was an increased number of citations from 1068
returns. to 7899 for veterinary pharmacology articles. The average
number of citations per article increased from 4.88 in the per-
iod 1975–1979 to plateau at 9–10 from the early 1990s to
VETERINARY PHARMACOLOGY: THE LAST 35 YEARS 2000 (Fig. 2).
Further analysis was undertaken using the search queries,
From a range of online citation indices, it is possible to derive ‘authors, countries, languages, source titles and subject area’.
useful quantitative information on the development of our dis- For countries/continents, veterinary pharmacology publications
cipline. For the period 1975–2010, the Web of Science (WOS) in the USA, EU and rest of the world have been approximately
has been explored. The initial input was the word ‘drugs’, equal, each contributing approximately one-third of the total
which was then further refined under either veterinary sci- over each 4-year period (Table 2). Of the 11 115 veterinary
ences or pharmacology, the latter providing a comparator for pharmacology publications identified for the period 1975–
the veterinary component of all citations in pharmacology. Of 2010, the language was overwhelmingly English (85.8%), fol-
814 631 publications for ‘drugs’, 205 684 were classified as lowed by German (5.6%) and French (2.5%). Regarding subject
‘pharmacology’ and 11 115 were selected in ‘veterinary area, the top five, in descending order for the 11 115 records,
sciences’. were pharmacology (6.70%), parasitology (3.89), zoology
Divided into successive 4-year periods, the ‘total’, ‘pharma- (3.85), toxicology (3.84) and agriculture (1.64%). For sources
cology’ and ‘veterinary science’ publications are illustrated in (journal titles), it is pleasing to note that Journal of Veterinary
Fig. 1. This demonstrates parallel trends for the three curves Pharmacology and Therapeutics leads with 6.70%, followed by
(note the logarithmic scale for the ordinate). The accelerated Journal of the American Veterinary Medical Association
increase in publications in the late 1980s–early 1990s was not (5.41%), with Veterinary Clinics of North America Small Ani-
a specific veterinary event but conformed, rather, to the gen- mal Practice (1.66%) in tenth position.
eral trend. Table 1 presents the ‘total’ number of articles Data for the 50 most cited veterinary pharmacology publica-
retrieved over nine periods between 1975 and 2010 for tions for the periods 1975–1979 and 1980–1989 and the 100
most cited publications for the periods 1990–1999 and 2000–
2010 can be supplied on request to PLT. In summary, the total
1 000 000 citation numbers for the most cited articles for these four peri-
ods were, respectively, 74, 102, 207 and 540. For the 1990–
1999 and 2000–2010 periods, even the publications in
100 000
Number of publicaƟons

position 100 had healthy citation numbers of 55 and 47,


respectively. Inspection of these tables reveals an initial pre-
dominance of interest in functional pharmacology (1975–
10 000
1989) involving analgesic, anti-inflammatory, anti-arthritic,
cardiovascular, respiratory and anti-epileptic drugs, but with
anthelmintic, antimicrobial and anticoccidial agents also well
1000
represented. Over the last 20 years (1990–2010), the emphasis
has shifted overwhelmingly to anthelmintic, antifungal and
100
antimicrobial drugs. For example, for the period 2000–2010,
1975 1980 1985 1990 1995 2000 2005 2010 17 of the 25 most cited articles concerned antifungal, anthel-
Years mintic, antimicrobial or anticoccidial drugs. Of particular
interest is the emphasis on the development of resistance to
Fig. 1. Numbers of publications on ‘drugs’ over nine 4 year periods
between 1975 and 2010 in three categories; ‘total’ (upper curve),
these drug classes. The numbers of articles with the word resis-
“pharmacology” (middle curve) and ‘veterinary science’ (lower curve). tance in the title for the 10, 25, 50 and 100 most cited arti-
Note that the ordinate is a logarithmic scale (data from Web of cles, over the four successive periods, were 5, 8, 12 and 21,
Science). respectively. Publications on analgesic and anti-inflammatory

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110 P. Lees et al.

Table 1. Analysis of publications and citations on ‘drugs’ over nine 4-year periods, 1975–2010*

Veterinary Vet Sci Average Vet %vet


Range of years Total drugs Pharmacol. Sciences Citations Sci Citations H-index* pharmacol

1975–1979 15 048 4833 219 1068 4.88 17 4.53


1979–1982 17 743 5346 306 1617 5.28 20 5.72
1983–1986 21 429 6211 366 2124 5.8 23 5.89
1987–1990 23 029 6619 413 2501 6.06 25 6.23
1991–1994 90 595 25 618 1550 16 424 10.6 49 6.05
1995–1998 110 620 29 110 1738 19 266 11.09 53 5.97
1999–2002 130 204 32 321 1872 21 505 11.49 58 5.79
2003–2006 170 804 41 334 2145 18 238 8.5 43 5.18
2007–2010 235 159 54 292 2506 7899 3.15 25 4.61
Total 814 631 205 684 11 115 90 642 Mean 5.55
SD 0.63

*Data from Web of Science.

100 ings and many textbooks. This source indicates that veterinary
Average number of citaƟons or H-index

pharmacology became ‘visible’ in terms of published research


output only in the mid-sixties. From 1964 to 1995, the num-
ber of publications increased slowly and progressively; then in
the late 1990s and beyond, there was a surge with a sixfold
10
increase from 1997 to 2007 (358 versus 2291 publications
Fig. 3). This was due to both a general increase in the number
of pharmacology publications and a specific increase in our
field with a percentage of veterinary publications that has
1
increased from 1995. The WOK database indicates that there
1975 1980 1985 1990 1995 2000 2005 2010 were three periods of interest for veterinary pharmacology:
Years 1950–1965, when there was a very low level of relative activ-
ity (<0.2% of all pharmacology publications); followed by the
Fig. 2. Average number of citations (lower curve) and H-index (upper
next 25 years (1970–1995) when the ratio was of the order of
curve) over nine 4 year periods between 1975 and 2010 in veterinary
0.5–0.7% of all publications in pharmacology; and a third per-
pharmacology (data from Web of Science).
iod 1995–2010 when the ratio was in the range 3–4%
(Table 3).
Figure 4 presents the H-index of publications in veterinary
pharmacology, obtained from the WOK database. This index
Table 2. Countries of publication for articles on veterinary drugs attempts to measure both the productivity and impact of pub-
between 1975 and 2010 (total number and percentage of total)* lished work. For example, in 1988, the H-index was 25, indi-
USA 3897 35.06% cating that for articles published in veterinary pharmacology
Germany 651 5.86% in that year, there were 25 articles that each received at least
England 644 5.79% 25 citations; beyond 2004, the H-index decreased, because
France 529 4.76%
these articles were recent; the H-index increases as citations
Canada 528 4.75%
accumulate, and thus, it depends on the ‘academic age’ of each
Japan 440 3.96%
Australia 336 3.02% publication. The general trend of the curve is increasing, at
India 274 2.47% least until 2000. It is concluded that veterinary pharmacology
Netherlands 270 2.43% articles have steadily become not only more numerous but also
Spain 249 2.24% more cited, at least until 2000.
*Data from Web of Science.
KNOWLEDGE DISSEMINATION THROUGH JOURNALS
drugs continue to be well represented in the latest 10-year AND LEARNED SOCIETIES
period (2000–2010), comprising 9 of the top 50 and 20 of the
top 100. Of very special note was the launching of Journal of Veterinary
Further information on the rapid development of veterinary Pharmacology and Therapeutics in 1978, under the editorship
pharmacology has been gleaned from another database, the of Charles Short and Andrew Yoxall. As well as our own jour-
Web of Knowledge (WOK). This gives coverage of 23 000 nal, the dissemination of knowledge in veterinary pharmacol-
academic and science journals, 110 000 conference proceed- ogy has depended on monographs, such as Veterinary Clinics

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Veterinary pharmacology 111

4000 60

3500
50
3000
40
PublicaƟons

2500

H-index
2000 30

1500
20
1000
10
500

0 0
1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010

Years Years

Fig. 3. Number of publications per year in veterinary pharmacology as Fig. 4. H-index of publications in veterinary pharmacology (data from
reported in the Web of Knowledge between 1960 and 2010. Web of Knowledge).

Table 3. Total number of publications in veterinary pharmacology, total The outset of this 35-year period, 1975–2010, also wit-
number of publications in pharmacology and percentage of veterinary nessed the pivotal formation of learned societies, devoted to the
publications over the total number of publications in pharmacology* advancement of and dissemination of knowledge within our
discipline: The American Academy of Veterinary Pharmacology
Vet. pharmacology
and Therapeutics (AAVPT), 1977; The European Association
as% of total
Vet. Pharmacology pharmacology for Veterinary Pharmacology and Toxicology (EAVPT), 1978;
Years publications publications publications and the Association for Veterinary Clinical Pharmacology and
Therapeutics in the UK also 1978. The European College of
1950 0 167 0
Veterinary Pharmacology and Therapeutics was formed in
1960 11 9022 0.122
1965 30 15 028 0.200
1997, as part of the programme for veterinary specialization in
1970 152 24 773 0.614 Europe, which had been encouraged by the Advisory Commit-
1975 221 40 109 0.551 tee for Veterinary Training (ACVT). More recently, the disci-
1980 282 44 426 0.635 pline has benefitted by the creation of further bodies, including
1985 310 50 090 0.619 the American College of Veterinary Clinical Pharmacology and
1990 358 62 474 0.573 the Chapter of Veterinary Pharmacology of the Australian Col-
1995 484 68 442 0.707
lege of Veterinary Scientists. These organisations hold major
2000 2041 69 777 2.925
2005 2709 77 573 3.492
congresses on 2–3 year cycles and regularly run educational
2010 3630 90 931 3.992 workshops in the intervening years.

*Data from Web of Knowledge.


THE NEXT 35 YEARS: PREDICTED AND DESIRABLE
of North America, and we note particularly the first edition of ADVANCES
the textbook, Veterinary Pharmacology and Therapeutics,
under the editorship of L. Meyer Jones in 1954. This was a As discussed by Jim Riviere (2007) ‘the field of veterinary ther-
landmark publication, because, as pointed out by Dunlop and apeutics is in a state of tremendous flux, being at the vortex of
Williams (1996), ‘veterinary medicine with few exceptions did strong currents arising from rapid technological advances,
not follow the human field in adopting pharmacology as an altered consumer perceptions on food safety and bioengineer-
experimental science until after the Second World War and the ing, and changing public attitudes towards the value of pet
first scientifically based textbook authored by L. Meyer Jones’. ownership; all occurring in an economic maelstrom, which is
This magnum opus continues to function as the veterinary changing corporate structure and forcing extreme cost efficien-
pharmacologist’s bible, now in its ninth edition (2009) under cies on the development, production and marketing of products
the editorship of Jim Riviere and Mark Papich (2009). targeted towards veterinary species’.
As Dunlop and Williams (1996) explained, the slowness of Developments over the next 35 years (2013–2048) might be
veterinarians to take up the new science of pharmacology considered from two perspectives, those that are ‘anticipated’
related to the fact that they, more than their human physician and those that are ‘desirable’, with inevitable overlap between
colleagues, were primarily concerned with treating microbial these categories. The desirable developments are relatively easy
infectious diseases. On the other hand, veterinary anaesthetists to state, whilst accurate prediction of developments is necessarily
were quick to take up the newly introduced local and general highly speculative. We asked several prominent leaders in veteri-
anaesthetics soon after their introduction; cocaine, ether and nary pharmacology for their thoughts. The results are presented
chloroform in the 19th and halothane, barbiturates, procaine in Table 4. Many of these thoughts of the great and the good
and lignocaine, in 3rd to 5th decades of the 20th century. need no further elaboration, and some developments are antici-

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112 P. Lees et al.

Table 4. The most important single advance in veterinary pharmacology/therapeutics over the next 35 years.

Colleague Advance

D. Church The use of species-specific whole genome scans to determine subpopulations based on differing sensitivities to
specific pharmacological compounds, thereby facilitating more appropriate ‘dosing’ regimens.
P. De Backer Innovation and development of new veterinary drugs, especially for large animals, are highly desirable, but there are
constraints due to increased legislation and the strong tendency for consolidation of companies in the pharmaceutical market.
F.M. Cunningham Ensuring the training and development of future generations of dedicated researchers and teachers in veterinary pharmacology.
J. Elliott Transcriptomics to identify new drug targets; genomics to predict which members of the patient population will respond to
recommended therapeutic dose; and proteomics to devise biomarkers of disease.
J.Fink-Gremmels Refinement of drug use (new application forms and devices), Reduction of the use of anti-infectives by preventive
measures (innovative vaccinations, modulation of the innate immunocompetence, bacteriophage therapy, etc.)
Replacement of general dose and application recommendations by individual therapeutic approaches.
J.N.King Use of modelling and other techniques to provide dosage recommendations for minor uses and minor species
M.F.Landoni Nanotechnology for drug delivery to ensure that drugs reach target sites in high concentrations, thereby reducing
systemic effects and for antimicrobial drugs avoiding drug resistance.
P. Lees Physiologically based pharmacokinetics (PB-PK), PK-PD modelling and population PK to optimize dosage schedules for
clinical use in animal subgroups, including individualization of dosage.
A.Livingston A switch from studying drugs acting on enzymes and receptors to investigating drugs acting on genes.
J. Maddison Antimicrobial drugs that are resistance proof.
M. Martinez Increased focus on mechanisms for manipulating transcriptional and translational processes, with implications for
treatment of physiological diseases, behavioural modification and cancer, immune modulation, as well as genetic testing
and applying novel delivery methods, including nanotechnology.
Q. McKellar An effective trypanocide with no toxicity to humans
C.Nebbia Gaining insights into interspecies differences in the expression of drug transporters to better explain species differences in
drug PK unrelated to phase I and phase II mechanisms.
M.Papich Improving the method by which regulatory agencies approve veterinary medications for animals, so that sponsors will be
encouraged to bring more compounds forward to meet the needs of animals and the veterinarians who treat them.
P.Reeves Advances in nanotechnologies with novel and beneficial applications in veterinary medicine.
J.Riviere Individualized and targeted drug therapy across all species, using miniature sensing and delivery devices, some with
embedded PK-PD algorithms or using nanodelivery platforms that provide local feedback on delivery mechanisms.
S. Soback Improvement of PK/PD-based dosing protocols to maximize efficacy and to justify scientifically extra label use of drugs.
P.-L.Toutain Pharmacodynamics will be the most important factor to prospectively develop new drugs having the appropriate selectivity;
as ‘omics’ sciences mature they will allow a comprehensive analysis of biological systems of many different species that
in turn will allow individualization. ‘omics’ will also impact on diagnostic and prognostics, and in toto, these factors
with those outlined by J.Riviere and P Reeves will change the face of veterinary therapeutics, provided that (a)
companies consider research and innovation as their pivotal role; and (b) regulatory authorities do not apply the brake
of the precautionary principle but rather seek to understand and facilitate innovations.

pated by several respondents. A common theme is the require- integrate population PK data with statistical models defining
ment to expand not only the range of veterinary medicines, but covariates, which identify the source of population variability,
also the adoption of novel means of delivering them, a theme fur- were described by Martin-Jimenez and Riviere (1998) and have
ther discussed in the next section of this review. been applied in several recent studies. Prominently expected
Physiologically based PK (PB-PK) models lend themselves to also is the impact of the ‘omics’ as disease markers, prediction
extrapolation of data between species and breeds, as they of response in individual animals and individualization of dos-
incorporate physiological and metabolic variables, such as age (Hindre et al., 2012; Sutton, 2012). Even if not fully real-
organ blood flow and hepatic biotransformation enzymes ized, these developments will provide drug manufacturers with
(Rowland et al., 2011). Recent veterinary examples include major challenges, so that constructive inter-relationships
prediction of: (i) withdrawal times for oxytetracyclin in sheep between regulators and regulated will be vital.
(Craigmill, 2003), (ii) tulathromycin in goats (Leavens et al.,
2011), and (iii) extrapolation of data on valnemulin in rats
to pigs (Yuan et al., 2010). PB-PK will create systems biology THE NEXT 35 YEARS: TECHNOLOGY-DRIVEN
approaches, incorporating genomic and proteomic data, ADVANCES
which will describe drug actions based on models from recep-
tor to the whole animal. When validated, these models will An international leader in the discipline of veterinary pharma-
allow in silico trials to reduce the number of whole animal cology recently predicted advances in veterinary therapeutics,
studies. based on six new transforming technologies (Riviere, 2007,
These developments will introduce an era of drug and dos- 2010). These are summarized in Table 5. Riviere emphasized
age selection to meet the requirements of within species, breed, the expectation of major breakthroughs through a combination
gender, age, weight and disease status differences. Models to of two or more of these areas to enable development strategies

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Veterinary pharmacology 113

Table 5. Impact of technological advances on future developments in veterinary pharmacology and therapeutics*
Technological advance Description and impact on veterinary pharmacology and therapeutics.

Computer technology Increased speed and quantity of data processing and integration of separate systems to facilitate (a)
dealing with large genomic data sets and (b) PK, population PK and PBPK models.
Microfluidics and miniaturisation Development of devices providing (a) complete analytical chemistry platforms on the size of a postage
of devices stamp, that is, ‘lab on a chip’, also described as micro-total analysis systems and (b) micro-electromechanical
systems for controlled drug delivery.
Nanotechnology Manufactured materials <100 nm diameter, possessing properties, providing targeted drug delivery systems
and microscale biological sensors.
High-throughput screening Combinatorial chemistry, involving libraries of hundreds (even thousands) of compounds, with a common
chemical motif are screened ‘en mass’ to identify (a) desirable PK properties or (b) compounds with the
greatest in vitro potency and/or efficacy and/or least toxicity.
Controlled and targeted drug Controlled release and targeted drug delivery is already well advanced in veterinary therapeutics and will be
delivery further refined.
Increased knowledge of Establishment of the genetic code of more animal species and breeds and of micro-organisms will enable the
pharmacogenomics specific targeting of drugs to animal and microbial species and the achievement of more specific endpoints.

*Adapted from Riviere (2007).

and yield novel products. The potential computer technology combines rapid exclusion of drugs with undesirable properties
advances have been discussed earlier. with consequently reduced development costs. These methods
Microfluidics will lead to the introduction of micro-total will be extended to the selection of veterinary drugs for next
analysis systems (TAS), which reduce sample sizes and stage development in more complex in vivo systems. It is
reagent volumes for quantitation and minimize hazardous expected that the potential for screening large numbers of
waste. Also, micro-electromechanical systems (MEMS) can be agents will be enhanced by the use of microfluidic and minia-
expected to lead to the introduction of implantable feedback- turised devices and possibly with nanotechnology and in silico
controlled delivery devices on a much smaller scale than cur- approaches. Rapid screening will also be extended to the field
rently possible. Such devices may be powered by absorbing of drug–drug interactions and has already been applied to the
ionic substances from the animal to charge internal batteries. field of genomics. The sequencing of a gene with 10 000 base
Microfluidic or miniaturized devices might be used to: (i) deter- pairs can now be accomplished in a few days, compared to
mine biomarkers of disease and facilitate individualization of 1 year 20 years ago.
therapeutics, (ii) detect specific genetic determinants of drug An excellent recent account of the many varieties of drug deliv-
resistance and thereby target drugs for the individual animal. ery systems currently applied in veterinary therapeutics has been
The latter might be coupled to microcomputers containing PK provided by Brayden et al. (2010). These range from osmotically
algorithms to optimize dosage regimens, being especially appli- driven minipump devices and reservoir-based polyethylene glycol/
cable to drugs with narrow safety margins. When used in drug systems for the intraruminal delivery of anthelmintics to
combination, TAS and MEMS devices might be used for insu- depot/sustained release formulations of antimicrobial drugs admin-
lin delivery with an on-board glucose sensor. All aspects of istered intramuscularly or subcutaneously. Of particular future
individualization of dosages will require the introduction of interest is the role of ABC efflux transporters in drug transport
new regulatory guidelines. mechanisms. Increased understanding of these pathways will facil-
The occurrence of chemical reactions on the surface of a itate the introduction of safer, more efficacious drugs and enable a
nanofibre will provide biological sensors linked, for example, to better understanding of drug–drug interactions. Riviere (2007)
specific antibodies, providing early warning of disease onset. points out that a commercial application of microneedles, which
Nanomaterials may also be developed to contain tissue target- puncture the skin without the chance of contamination or produc-
ing molecules for treatment of organ-based cancers. Their high tion of any sensation, may provide a novel means of transdermal
surface reactivity on a weight basis may provide for scavenging drug delivery.
applications, for example of toxins or oxygen free radicals. The Riviere (2010) and Mosher and Court (2010) have reviewed
PK of nanomaterials will require further study, however, as tis- recent advances in comparative and veterinary pharmacoge-
sue uptake seems to be related more to mechanisms of cellular nomics. It is clear that further advances in genomics, proteomics
uptake, for example by vesicular transport, than to blood flow. and metabolomics will be fundamental to development of the
Their poor elimination from the body will also need to be next generation of more efficacious, selective, safer and targeted
addressed from a toxicological perspective. Their particulate veterinary drugs. As Riviere (2007) points out, all of these devel-
and hydrophobic character may lead to clearance primarily by opments will depend not only on scientific advances, commercial
the lymphatic system. potential and acceptance by societies, but also on an enlightened
High-throughput screening to identify desirable PK or PD approach of national regulatory authorities. Moreover, without
properties is already used extensively in the initial stages greater international harmonization of regulatory guidelines,
of human drug development programmes. The approach the development costs alone will prevent the introduction of

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114 P. Lees et al.

many potentially useful novel agents and delivery mechanisms. ing experience but a necessary one. For example, if the interest
As Riviere (2007) states ‘the global harmonisation of animal is pain control or antimicrobial therapy, the researcher will be
drug regulations would, at a stroke, remove impediments to well advised to improve his/her knowledge of pain mechanisms
rapid drug approval and subsequent marketing’. and pathways and those aspects of the biochemical and molec-
ular processes in micro-organisms, which provide potential tar-
gets for drug action, respectively. Moreover, such knowledge, if
CONCLUDING RECOMMENDATIONS AND GUIDELINES not always acquired at the deepest level, will be necessary to
FOR OUR YOUNG COLLEAGUES FOR A SUCCESSFUL facilitate collaboration with colleagues from related disciplines.
CAREER IN VETERINARY PHARMACOLOGY Relevant here is the ‘one-health concept’; this is likely to
increase the interest of colleagues outside our fields in veteri-
On history, we note the comment of Winston Churchill that nary pharmacology and toxicology, as disciplines governing
‘the further backward you can look, the further forward you the multifaceted interactions and links between animals and
are likely to see’. We refer our young colleagues to the pioneer- man, animals and the environment and acceptable and safe
ing work and writings of those greatest of all biologists, Charles food supplies.
Darwin and Louis Pasteur, as the individuals who laid the In summary, the major task of veterinary pharmacologists is
foundations for all modern biological disciplines. to tackle the continuing challenge in improving our under-
On serendipity, we emphasize that the most exciting results standing of inter- and intra-species differences and the task will
are often the most unexpected; the experiment that fails to be to signal individual variability (including the variability
confirm the hypothesis may offer the best prospects for new within and across animal populations) in PK and PD to our
advances. clinical colleagues, and thereby to translate fundamental
On data, we ask our younger colleagues to reflect carefully insights into drug action and fate into clinical therapy.
on the nature of data, on how to generate, observe, interpret And finally, we note the advice of the 17th century philoso-
and use it. For example, when using the excellent available pher of science, Francis Bacon, ‘if a man will begin with cer-
programmes for analysis of PK and PD data, remember the tainties, he will end in doubt; if a man will begin with doubt,
adage ‘rubbish in ……. rubbish out’. In 1871, the physicist he will end in certainties’.
Lord Kelvin (who gave his name to the °K absolute tempera-
ture scale) told us to forget the ‘eureka moment’ of scientific
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