08/08/2023
Dear FRIENDS ALL,
I am very excited to bring you this important and readable article written by Leslie Rugg. Please do comment and post any questions you have! I am grateful to Leslie for her permission to share this critical information with all of you. Knowledge is power and with it we can all work together to ensure a secure future for the collie breed we love!
PLEASE SHARE THIS POST!
Thank you ALL!
Hugs & Wags, Leslie
“Above all, do no harm”
by Leslie Crane Rugg
August 2023
What do Acepromazine, Butorphanol, Cyclosporine, Dexamethasone, Erythromycin, Galliprant,
Ivermectin, Loperamide, Methylprednisolone, Selamectin, Tetracycline, and Vincristine all have in common? These drugs, many used for decades, have helped treat dogs and humans alike. They are all marvels of medicine. Yet this alphabet soup of drugs has something else in common. When given to people and dogs whose blood-brain barrier is damaged, defective, or disrupted, they cross the barrier from the bloodstream into the brain, causing an assortment of toxic reactions in dogs from stupor to seizures to death in many instances. But is that all that happens?
Only twenty years ago, a veterinary researcher identified the mutated multi-drug resistance gene (MDR1) responsible for affecting p-glycoprotein (P-gp), the pump that in healthy dogs sustains the integrity of the blood-brain barrier. This researcher, Katrina Mealey, DVM, PhD., DACVIM, DACVCP, eventually developed a test for dogs, determining which were affected by, clear of, and/or passing on this inherited mutation to their offspring.
Breeders, owners, and even veterinarians assumed the test to be useful as a tool to know what drugs collies might be sensitive to or intolerant of. Many people concluded that testing was really not necessary; they could simply and safely assume that collies in general should avoid those questionable, potentially toxic drugs, identified by Mealey and her Washington State University team. Other people, especially breeders who made health a prominent factor in their breeding programs, began to test their breeding stock and then their litters to learn how the genetics of the mutation bore out among their puppies.
That might have been the beginning and end of this particular aspect of collie health...except that only a few years after Mealey's discovery and test development, veterinary researchers began to look for other connections beyond drug sensitivity that a compromised blood-brain barrier might affect. The results are significant and alarming. The weakening or breakdown of the blood-brain barrier ends up playing a substantial role systemically throughout a collie's body. Here, in brief, is a summary of only some of the research results correlating the mutated MDR1 gene with yet another alphabet soup of very serious diseases and conditions:
A veterinary study published in 2010, entitled “Blood-brain-barrier disruption in chronic canine hypothyroidism,” took a small group of 18 mixed breed female dogs with normal thyroids, dividing them evenly between control and variable subjects. The variable group was given iodine to induce hypothyroidism, and among that group cerebrospinal fluid abnormalities and evidence of cerebrovascular disease were found. The researchers concluded that the integrity of the blood-brain barrier was indeed disrupted in cases of chronic hypothyroidism.
More recent National Institutes of Health (NIH) studies include one published in Epilepsia in 2019 that correlated the relationship between blood-brain barrier dysfunction and canine seizures. In the last two years, other studies helmed by Erez Hanael link blood-brain barrier dysfunction with canine brain tumors and meningoencephalitis (inflammation of the brain and brain lining). A relationship also exists between canine liver disease and brain disorders: when built-up ammonia, with no other way to exit the body, crosses a damaged blood-brain barrier, it can lead to brain and mental function degeneration. Diagnosed with hepatic encephalopathy, collies tragically experience unsteadiness, excessive drooling, seizures, and even sudden blindness.
Let's also take a second look at some the drugs we now know to avoid in order to understand how they can affect our collies' lives. Metronidazole is a go-to antibiotic traditionally used by veterinarians to treat severe cases of diarrhea, resulting from giardia for example, as well as other parasite-based, inflammatory conditions and some bacterial infections. You may be surprised to learn that this drug has never been FDA-approved for dogs but has been used off-label for decades by veterinarians. You may also have heard that some collies seem to tolerate Metronidazole while others do not.
Now we know why. The MDR1 mutation increases the likelihood if not the certainty for dire neurological side effects. Ten years before the mutation was discovered and testing became available, a friend of mine took her two rough collies to their veterinarian to diagnose and treat worsening diarrhea. The veterinarian determined giardia as the cause and prescribed high doses of Metronidazole, course after course, to get rid of the parasites. Instead both dogs died.
Phenylpropanolamine (PPA), another off-label drug used by veterinarians to combat canine urinary incontinence, was known as far back as 1992 to pe*****te the blood-brain barrier, based on a study using rats. Yet that was the drug of choice given to two of my collies (one male, one female) when both became incontinent in the mid 1990s. PPA surely worked its magic. Yes, their incontinence lessened, but, after several months on the drug, they began to have short seizures. Weaning them from the drug, minute increment by minute increment, seizure by seizure, took time, but they survived. In hindsight, I realize both collies must have had the MDR1 gene mutation – most likely as Normal/mutant because they did not experience worse side effects and never had another seizure once clear of the drug.
Now fast-forwarding to the 2020s, new cancer-fighting drugs and flea/tick preventives in the neurotoxin class of isoxazolines have come along, beneficial to many breeds but not to our MDR1 mutant collies. Many gold standard drugs used in canine cancer treatment were among the first to be identified as ones to avoid. New wonder drugs for lymphoma, mast cell tumors, and sarcomas give many dogs improved survival rates but can't be used for MDR1 collies, substantiated by Jerold Bell, DVM, renowned veterinary geneticist, at a seminar hosted by the Collie Health Foundation at the 2022 Collie Club of America National Specialty. In his lecture on genetic disease control, Bell further noted that the main drug used for tick-borne diseases must also be avoided. Collies are left with less effective drug protocols because of the MDR1 mutation that compromises the blood-brain barrier.
Recent evidence regarding heartworm and flea and tick preventives is similar. According to the U.S. Food & Drug Administration, some dogs present neurologic adverse reactions, including muscle tremors, ataxia, and seizures after being dosed with preventives such as Bravecto (fluralaner) tablets and topical solution, Credelio (lotilaner) tablets, Nexgard (afoxolaner) tablets, Simparica (sarolaner) tablets, and the triple whammy of Simparico Trio (sarolaner, moxidectin and pyrantel) tablets.
Yet a study conducted by a veterinary hospital group in conjunction with a research university suggested that Moxidectin, a newer heartworm preventative, might be safer than other preventives for dogs with the MD1 gene mutation. That might well indicate that Moxidectin by itself in a specific low dose might not produce the same degree of toxic reaction for Normal/mutant collies. However, studies have proved that the neurotoxin aimed at a parasite doesn't only affect the parasite but the host as well.
Again, in dogs where the blood-brain barrier is not intact, poison invades the brain – it's that simple. The same may be true of Galliprant, now widely used as an anti-inflammatory for arthritis, but only tested on healthy dogs. This drug may only be safe for MDR1 mutant collies in very low doses.
Looking at these studies and anecdotal accounts of the systemic response that can occur when the blood-brain barrier is disrupted, we can't say having and producing collies with the MDR1 mutation is a minor inconvenience. The mutation is not equivalent to seasonal air-borne allergies or getting a hot spot. MDR1 has systemic significance, capable of affecting all parts of a collie's body...and the list of toxic medications and chemicals continues to grow. The Collie Health Foundation states on its MDR1 mutation webpage that “MDR1 doesn’t just affect the brain. P-gp is also present in dogs’ guts, liver and kidneys. In the gut, P-gp restricts absorption of drugs while, in the liver and kidneys, it promotes their excretion. MDR1 mutant dogs therefore absorb more and excrete less drugs than their unaffected counterparts. Recent research has shown that MDR1 status also affects cortisol metabolism.”
In fact, in the Summer 2023 issue of the Collie Health Foundation newsletter, an article explains how cortisol freely enters the brain of collies with the MDR1 mutation, simultaneously lowering cortisol in the blood where it should be. In the same article, a 2022 German study was cited that found cortisol in affected collies' urine. Together these findings point toward a possible predisposition for adrenal gland insufficiency and a potential correlation with Addison's disease. Veterinary science shows that the mutation makes our collies vulnerable to a host of organ and system catastrophes.
it is vital for collie owners to share information about MDR1, its consequences, and the test with their veterinarians. The MDR1 test is not solely a diagnostic tool to determine if collies can't tolerate certain drugs and chemicals. It is also a breeding tool to help collie breeders work toward weeding out a serious malfunction that opens our collies up to an expanding number of health challenges. It does matter whether sires and dams are mutation-free with two healthy MDR genes to pass onto their get, or affected with the mutation that they will pass on to their offspring, or are at risk for toxic reactions having inherited one healthy and one mutant gene and will pass the mutation on to their litters. The genotypic breakdown in litters is described on the Washington State University/MDR1 litter testing webpage.
In Bell's lecture, he spoke directly to breeders, applauding those who have tested their collies over the last twenty years. However, statistics also show that test results have not been applied to breeding programs. Bell acknowledged that breeders may be testing more, but he was equally concerned that breeders are not reducing or eliminating the MDR1 mutation. Instead the mutation is appearing with the same regularity in subsequent generations of litters as had appeared before the mutation was identified.
With more studies revealing the key value of a healthy blood-brain barrier, isn't a simple blood test about the MDR1 gene worth doing? A breeder's duty can't stop there. If the mission of collie breeders is to preserve the breed and ensure its future, then it is advantageous both to breeders and the collies they produce to make wholesale use of genetic knowledge now at hand. Bell firmly cautioned his audience, “Do not produce affected animals; decrease the frequency of defective genes.” Bell further affirmed that it is possible to “maintain the quality of your breed while decreasing genetic disease.”
Normal/Normal is achievable without sacrificing an entire breeding program. Ask the collie breeders who have successfully met that goal by not breeding mutant/mutant collies and selectively breeding their Normal/mutant stock to produce Normal/Normals. Those breeders have made the commitment to produce the healthiest collies possible without sacrificing beauty. Both are possible to attain when art and science together are a breeding program premium. Shouldn't our collies look good, feel good, have a constitution that protects them from terrible consequences, and be assured a happy long life? We all have a responsibility to be educated and pass along important information to all who love and serve our breed – owners, breeders, and veterinarians.
On a personal note, I've loved collies practically all my life, starting at the age of 5. Currently, collies number 13 and 14 grace my life. I don't believe life is worth living without a collie enriching it.
I never bred a litter; my husband knows I would have kept all the puppies. None of my collies achieved their championships. When they developed a health problem, I stopped showing since they no longer represented the future of the breed. Regardless, I loved them dearly all of their lives.
All collies deserve to have quality of life. To that end, every collie member of my family since the MDR1 test became available has been tested. That accounts for my last four collies: two with the mutation (one male/one female) and two Normal/Normal (one male/one female). Because so many of the collies in my life (from a variety of bloodlines) have been diagnosed with hypothyroidism – 10 out of 14 – I had always wondered if a connection might exist between the MDR1 mutation and thyroid disease. Isn't it interesting that, among my very small group of four collies, the two with the mutation are also hypothyroid, while the two MDR1 Normal/Normal are thyroid-normal! Purely a coincidence or an emerging pattern? Now that I know about that 2010 study, I may just have an answer.
Leslie Crane Rugg calls herself a collie person. As a writer, she has owned, written for, and been editor-in-chief of a collie breed magazine and co-owned, written for, and been editor-in-chief of a rare breed magazine. As a freelance writer, her articles have been published in major mass market and breed world animal magazines and on websites. She also co-authored five novels, published by Pocket Books. As an educator, she has taught and tutored students from pre-school through graduate school, learning challenged to enrichment, in subjects including developmental skills, executive function, time management, reading, literary criticism, history, and a variety of humanities and social sciences. She also worked closely with Bob Weatherwax and his two last “Lassies” as a promoter, manager, and pedigree researcher. More recently she has written grants and feature magazine articles for avian nonprofits.
References
Bell, Jerold S. DVM. “The Ins and Outs of Pedigree Analysis, Genetic Diversity, and Genetic Disease Control.” Collie Club of America Breed Education Committee in association with the Collie Health Foundation. 2022 Collie Club of America National Speciality. www.youtube.com/watch?v=vc1uyI_8xs0
“Brain Disorder Due to Liver Disease in Dogs.” Wag! / Wag Lab Inc. 2023. https://wagwalking.com/condition/brain-disorder-due-to-liver-disease
Brooks, Wendy, DVM. “Grapiprant (Galliprant).” Veterinary Partner / VIN. Revised 6/18/2023.
https://veterinarypartner.vin.com/default.aspx?pid=19239&id=7933279
“Collie Health 101: MDR1.” Collie Health Foundation. www.colliehealth.org/mdr1-mutation/
Daneman, Richard and Alexandre Prat. “The Blood-Brain Barrier.” Cold Spring Harbor Perspectives in Biology. 2015 Jan; 7(1): a020412. NIH National Library of Medicine / Pub Med Central. www.ncbi.nlm.nih.gov/pmc/articles/PMC4292164/
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