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Ivermectin Revisited
(Multi-drug sensitivity in Collies and related breeds)
by Pat Hutchinson
Recent research in America and Europe has revealed that in addition to Collies several other breeds,
believed to share the collie lineage, are susceptible to the dangerous side effects of a variety of
therapeutic drugs, including Ivermectin.
A team of American Veterinary geneticists, headed by Dr Katrina Mealey and Dr Mark Neff, has been
researching canine multi-drug resistance since the late 1990’s. Towards the end of 2003 Val Geddes and I were
approached by Mark and asked to collect DNA samples from UK Collies and related breeds.
The research findings make interesting reading, especially in relation to the origins of the affected breeds. Mark
has kindly allowed us to condense and simplify the findings, and extracts from the research paper are used
where relevant.
Terminology:
Chromosomes: Within the nucleus or ‘power house’ of all body cells are fine, random twisted threads of DNA known
as chromosomes. There are 39 pairs of similarly constructed chromosomes in all cells except the sex cells (eggs and
sperm), where the 39th pair are the sex chromosomes X and Y.
Genes: On closer examination the chromosomes are subdivided into segments known as genes that are units of heredity.
Each gene is responsible for a specific characteristic or trait eg. eye colour, hair type etc.
Locus: This is the position of a specific gene on a chromosome. For example, the gene for eye colour occupies the same
locus on each of a pair of chromosomes, and each of a pair of genes is known as an allele.
Gene Mutations: Rare occurrences and are usually, but not always deleterious. Closely related dogs have increased
chances of receiving the same copy of both mutant and normal genes, which explains the prevalence of breed-related
genetic disorders. As close inbreeding and line breeding are necessary to fix desirable traits, a higher percentage of
defective offspring may also be produced.
Blood-Brain barrier (BBB): Over one hundred years ago biologists discovered that if a blue dye was injected into an
animal’s blood stream the tissues of the whole body, except the brain and spinal cord, turned blue. They discovered that
the BBB is not a single structure or membrane but is created by the way in which the cranial blood vessels are
organised in the brain. The BBB acts as a natural defence mechanism for the brain and central nervous system,
protecting them from toxic substances in the blood stream, whilst supplying them with the required nutrients for correct
functioning. The BBB limits the rate at which therapeutic drugs permeate into the brain but if the BBB is malformed,
due to a genetic disorder, drugs such as Ivermectin are unable to be pumped back out of the brain. They filter into the
central nervous system causing toxic reactions, paralysis and even death.
* “Breed distribution and history of canine mdr1-1∆, a pharmacogenetic mutation that marks the emergence of breeds from the collie
lineage” by Mark W. Neff*, Kathryn R. Robertson*, Aaron Wong*, Noa Safra*, Karl W. Broman†, Montgomery Slatkin‡, Katrina L.
Mealey§, and Niels C. Pedersen*(*The Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California, Davis,
CA 95616; †Department of Biostatistics, Johns Hopkins University, Baltimore, MD 21205; ‡Department of Integrative Biology,
University of California, Berkeley, CA 94720; and §Department of Veterinary Clinical Sciences, College of Veterinary Medicine,
Washington State University, Pullman, WA 99164).
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Ivermectin is a form of antibiotic, originally produced from a fungus isolated in a Japanese soil sample. Its antiparasitic properties were welcomed by the veterinary profession and the new ‘wonder’ drug was licensed in the
USA in 1983 under the trademark Ivomec. Ivermectin was found to be extremely effective in eliminating
certain types of nematodes and arthropod parasites (worms and ticks) in cattle, pigs, and horses. The drug
worked by exerting anti-parasitic action in the peripheral nervous system of the parasites causing them to
become paralysed and die.
The treatment was so successful that some veterinary surgeons began to use Ivermectin to treat canines against
worms, ticks and mange mites, despite the fact the drug was not licensed for them. In most instances there were
no problems but suspicions were aroused when some dogs, especially some collies and related breeds, became
extremely ill or died as a result of this treatment. Symptoms of Ivermectin poisoning in dogs include excessive
salivation, ataxia, blindness, coma, respiratory compromise, and even death.
Ivermectin comes in several forms – an injectable version for cattle and pigs; oral paste for horses; oral
drenches for sheep; and oral tablets for the prevention of canine heartworm disease. The drug only partially
metabolises in the liver, resulting in the majority being excreted in the faeces. In cattle, sheep and horses
significant amounts of Ivermectin can remain in the faeces so it is of paramount importance that dogs should
not be allowed to ingest animal dung (in 2004 a Rough Collie died of Ivermectin poisoning resulting from
ingesting horse faeces).
Early research revealed a pre-existing mutation of the multi-drug resistance gene (MDR1), which affects the
functioning of the blood-brain barrier. Although Ivermectin is generally safe for use in domestic animals, some
dogs apparently have mutations of the MDR1 gene (known as mdr1-1Δ) and could therefore have problems.
“The earliest indication that ivermectin neurotoxicity was caused by a defect in the blood-brain barrier came
from an observation that affected dogs had elevated concentrations of ivermectin in the central nervous
system”. A principal component of the blood-brain barrier is P-glycoprotein, an independent drug-transporter
that enables drugs to be pumped in and out of the brain. At least twenty known therapeutic drugs, some of
which are listed in Table 1, usually pass safely through the blood-brain barrier but a dog possessing the mutant
gene is unable to pump some of these drugs back out of the brain and so they filter into the central nervous
system causing toxic reactions.
Therapeutic class
Examples
Anti-parasitic drugs
Avermectins eg Ivermectin*
Selamectin*
Moxidectin*
Erythromycin
Grepafloxacin
Doxorubicin*
Vincristine*
Vinblastin
Cyclosporin A
Tacrolimus
Dexamethasone
Hydrocortisone
Loperamide* (Immodium)
Domperidon
Quinidine
Digoxin
Ondansetron
Anti-microbial agents
Anti-cancer agents
Immunosuppressants
Steroids
Gastrointestinal drugs
Cardiac drugs
Narcotics
Table 1: Therapeutic drugs that normally pass safely through the blood-brain barrier
*Those drugs which are known to interact with the canine mutant multi-drug resistance gene, mdr1-1Δ, and cause problems.
(Katrina Mealey has recently been working on mdr1 interactions with Loperamide and she recommends breeders take note as mutant dogs
can have major problems when given Loperamide. A European country is about to market a veterinary form of Loperamide, which could
become another problem for collie breeders).
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The mutant gene, (mdr1-1Δ), had previously been associated with drug sensitivities in two breeds from the
collie lineage. Reports of drug sensitivity in other purebred populations were surveyed and the same mutation
was found in seven additional breeds, including two sighthounds (Table 2) that were not initially thought to
share collie ancestry.
The American research team surveyed selected dog populations based on their presumed relatedness to the
Collie and DNA samples were collected from more than 4000 purebred dogs, representing 164 breeds. Samples
were obtained from a repository at the Veterinary Genetics Laboratory (University of California) and from
members of affected breeds on both sides of the Atlantic. Volunteer breeders and owners were enlisted to
distribute buccal swabs for the collection of DNA samples, which were then surveyed for the presence of the
mutant gene. “….Four classes of dogs were tested: first, breeds from the collie lineage that were selected
based on a composite of breed histories (see Fig. 1. The Ancestral Relationships of British Herding Dogs);
second, European herding breeds that were not thought to be closely related to the Collie; third, sighthounds
and miscellaneous breeds that had exhibited drug sensitivities, often in response to ivermectin ;…… and fourth,
a multi-breed panel composed of over a thousand samples from more than 90 breeds…”
Breed
Australian Shepherd
Australian Shepherd (Miniature)
Collie
English Shepherd
McNab
Old English Sheepdog
Shetland Sheepdog
Longhaired Whippet
Silken Windhound
No. Tested
178
56
263
91
35
151
190
89
84
% affected
16.6
25.9
54.6
7.1
17.1
3.6
8.4
41.6
17.9
Table 2: Seven breeds of the Collie lineage and two sighthound breeds which are predisposed to
the mutant multi-drug resistant gene mdr1-1Δ
(Research into multi-drug sensitivity in Collies, carried out in Holland and Germany, DNA sampled three hundred
Collies. 47% possessed the mutant multi-drug resistance allele mdr1-1Δ, 20% were normal and 33% were ‘carriers’).
The frequency of the mutation varied from less than 4% in the Old English Sheepdog to more than 50% in the
Collie.The similarly high frequencies of the mutant allele, in both British and American Collies, suggests that
the mutation entered the Collie gene pool around the time the breed was formally becoming established in
Great Britain. Shetland Sheepdogs and Old English Sheepdogs, which also share the working collie lineage,
apparently exhibit ivermectin sensitivity as do several non-herding breeds. Although there were fewer available
samples from UK Shetland Sheepdogs and Old English Sheepdogs, mutations appeared to be more frequent in
the British subpopulations. “…The allele was not found in the Border Collie, Bearded Collie, or Australian
Cattle Dog, three collie-related breeds that have reportedly exhibited ivermectin sensitivity….. The presence of
occasional drug sensitivity in these breeds implies that mdr1-1Δ may be present at low frequency, or that
another mutation is responsible……”
“…..In contrast, the mutation was not found in any of the herding breeds whose origins traced back to
continental Europe. The allele was, however, detected in two non-herding breeds, the Longhaired Whippet and
the Silken Windhound, which were among the sighthound class of breeds tested because of anecdotal reports of
ivermectin sensitivity.” Results suggested that Collies have therefore been carrying the mutation for much
longer than the sighthound breeds. The Longhaired Whippet and Silken Windhound findings imply an ancestral
connection between the two breeds so their origins are worth noting here. Longhaired Whippets, restored in the
1950’s by a single breeder (who also raised Shetland Sheepdogs), were used during the development of the
Silken Windhound suggesting the Shetland Sheepdog is likely to be the source of the mutation.
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“History of the mutation. “…Dogs carrying mdr1-1Δ share a common ancestor that experienced remarkable
evolutionary success, having contributed genetically to at least nine distinct breeds of dog. We propose that
this animal lived in Great Britain in the 1800s, before the emergence of formal breeds. Before 1870, there were
no established registries for sheepdogs, only regional varieties of working dogs that had been adapted to
terrain, climate, breed of sheep, and working style. Industrialization in the 19th century brought changes in
trade and transportation that may have facilitated admixture among these varieties. Socioeconomic changes
almost certainly altered the role of working dogs as they were no longer needed to drive sheep over long
distances to market. Although a few specialized strains rose in prominence, perhaps aided by success at field
trial events, many strains such as the Galway Collie, the Dalesman, the Manx Sheepdog, and the Welsh Grey
gradually began to disappear. The neglect of regional varieties may have contributed directly to the advent of
dog shows, which aimed to preserve and restore strains by emphasizing form rather than function. The first
bench show to admit herding dogs took place in Birmingham in 1860, with one class open to all “sheepdogs,
colleys, yard or keeper’s dogs” *.
This show marked the beginning of an important transition in the history of sheepdogs, from regional variety to
registered breed, and from anonymous working dog to pedigreed purebred ……. .The first formal breeds to
emerge from working sheepdog populations were the Collie, Old English Sheepdog, and Shetland Sheepdog.
Several influential founders of the Collie breed, such as Old Cockie and Trefoil, were born in the 1860s ….
According to Baskerville, “Next to nothing was known of the pedigrees of the afore-mentioned dogs except that
the majority of them came from a working strain of sheepdogs”…. Working collies contributed genetically to
the Shetland Sheepdog, which probably accounts for the presence of mdr1-1Δ in the latter breed. Thus the
allele may have already been prevalent among working collies by the 1890s. The Old English Sheepdog was a
founding member of the Kennel Club of England in 1873, and has probably been genetically isolated from
other collie-related breeds since that time. Unlike the Shetland Sheepdog, the Old English Sheepdog is distinct
from the Collie in size, shape, and behavior, so registered show Collies are unlikely to have been the source of
mdr1-1Δ. Rather, admixture among the working progenitors of these two breeds is the more likely
explanation…..The ancestors of the Australian Shepherd, English Shepherd, and McNab also trace back to this
ancestral population….. Although these latter breeds were developed in North America in the 1900s, they were
most likely derived from nondescript farm collies imported from Great Britain and Australia in the 1800s and
early 1900s. Several lines of evidence suggest that the mdr1-1Δ mutation event predated the formal
establishment of British herding breeds, beginning in 1873……”
This article is not intended to start a ‘witch hunt’ but has been published to ensure we have a better
understanding of the problems of multi-drug sensitivity in Collies. It is now possible for us to establish whether
our own dogs may be susceptible to certain drugs and, in the researchers’ words: “ An understanding of the
genetic basis of differential drug response can be used to identify individuals that might be predisposed to
adverse drug effects. Veterinarians can use DNA testing of mdr1-1Δ, to screen animals before administering
certain therapeutic drugs. Denying entire breeds an effective treatment, which is currently done with
ivermectin and herding breeds, is now unnecessary….”
*Herding Dogs: Their Origins and Development in Britain. Iris Combe, Faber & Faber 1987
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Case History
During the late 1980’s Mary Farnes (Coppi Collies) had a traumatic experience with Ivermectin and, as a
result, was instrumental in having the labelling on Ivermectin amended to include a warning as to its possible
detrimental effects on Collies. The following case history is taken from an article published in the 1989
International Collie Handbook, entitled “Ivomec -To Kill or Cure”, and is reproduced here by kind permission
of Mary Farnes and Audrey Chatfield:
“In 1987 we purchased a Rough Collie bitch. In November 1988 this bitch produced a litter. The puppies,
whilst being quite healthy, did not appear to respond to the normal worming treatments. On the advice of our
vet we treated all of the pups with the broad spectrum wormer Lopatol. All of the puppies improved………As a
consequence of this the vet advised that we should also treat our 3 other adult Rough Collie bitches with a
broad spectrum wormer. He suggested a new ‘wonder drug’ he had been using for the past twelve months with
no ill effects on the dogs he had treated….
7 February 1989 – The 4 adult dogs were injected by our vet against worms.
8 February - ………24 hours after the injections the first dog ‘Jabberwocky’ collapsed and gradually during
the next 7 hours became paralysed and comatose………Poison was at first suspected, either from something
they had eaten on their walk or perhaps lead from roof repairs. The other dogs appeared quiet but were eating
and moving with no problems.
9 February – Jabberwocky still comatose…….. ‘Democat’ now seems un-coordinated but is on her feet and is
eating.
1I February – Jabberwocky now blind – Democat becoming semi-comatose but is able to eat although her
breathing was laboured……..The other dogs are quiet and depressed. Although the injection is suspected MSD
(Merck, Sharp & Dohme -manufacturers of Ivomec) and our vets are discussing dosages rather than corrective
action.
12 February – Democat now unable to walk or eat……….Later in day also becomes blind and paralysed.
14 February – Jabberwocky died – Discovered for the first time that the drug used was Ivomec…..
22 February – Democat died…….
Two of the four dogs unfortunately succumbed to the drug whereas the other two bitches gradually recovered
with no apparent after effects.”
P.S. The comment ‘with no apparent after effects’ is slightly misleading as Mary apparently did have a
problem with one of the bitches at a later stage. “ Prior to being given Ivermectin, ‘Copycat’ had produced
three litters of clear-eyed puppies. Her subsequent litter were all born with holes in the backs of their eyes.”
Discussions between Mary, her vet and MSD-Agvet (the UK distributors of Ivomec) resulted in MSD
amending its advice to users by adding warnings to its labelling. In a letter to the Editor of the Veterinary
Record, dated 5 October 1989, WG Ryan of MSD-Agvet, New Jersey, USA, and P Harlech Jones of MSDAgvet , Hertfordshire, stated:
“IVERMECTIN USE IN COLLIE DOGS
In the UK, a range of formulation of Ivermectin is registered for use in cattle, sheep, goats and horses
…….and in pigs………At present there is no formulation of Ivermectin registered in the UK for use in
dogs……..some dogs within the collie breeds have an idiosyncratic and potentially fatal susceptibility to
Ivermectin…………use of Ivermectin should be restricted to the indications included on the data sheet. In order
to further discourage extra-label use, the following statement will be added to the package insert for the cattle
product.
IVOMEC injection for cattle is a low volume product registered for use in cattle. It should not be used in other
species as severe adverse reactions, including fatalities in dogs, may occur.
An equivalent warning will also be added to the package insert of IVOMEC injection for pigs”
Such letters to the ‘Veterinary Record’ are often the only means by which vets keep up to date with veterinary
progress.. Mary wishes to make it quite clear that her vet, as a lone practitioner, had not previously heard of
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problems with Ivermectin. It was she who had informed him about the issues surrounding Ivomec, despite
MSD insisting that they were not responsible.
It is therefore vitally important that breeders keep each other, and their vets, informed of health issues affecting
our Collies.
References
The Research Paper - “Breed distribution and history of canine mdr1-1∆, a pharmacogenetic mutation that
marks the emergence of breeds from the collie lineage”
by Mark W. Neff, Kathryn R. Robertson, Aaron Wong, Noa Safra, Karl W. Broman, Montgomery Slatkin,
Katrina L. Mealey and Niels C. Pedersen.
‘Ivomec – To Kill or Cure’ – Mary Farnes (International Collie Handbook 1989)
‘The Collie – A Veterinary Reference for the Professional Breeder –Sharon Lynn Vanderlip D.V.M. 1984
Web sites:
www.pnas.org/cgi/reprint/0402374101v1 -the actual research paper in pdf format
www.vetmed.wsu.edu/depts-VCPL/#Breeds - general information on Ivermectin and other drugs
http://faculty.washington.edu/chudler/bbb.html - blood-brain barrier for beginners
http:/users.ahsc.arizona.edu/davis/bbb.htm – the blood-brain barrier