Multi-Drug Sensitivity in Collies and Related Breeds- the Iverm

Ivermectin Revisited

(Multi-drug sensitivity in Collies and related breeds)

by Pat Hutchinson

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.

* “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).

Ivermectin is a form of antibiotic, originally produced from a fungus isolated in a Japanese soil sample. Its anti-parasitic 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.

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).

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…”

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 mdr1-1Δmaybe 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.

“History of the mutation.“…Dogs carrying mdr1-1Δshare 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 mdr1-1Δmutation 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

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 MSD-Agvet , 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 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:

-the actual research paper in pdf format

- general information on Ivermectin and other drugs

- blood-brain barrier for beginners

http:/users.ahsc.arizona.edu/davis/bbb.htm – the blood-brain barrier