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MDR1 - can we eradicate?

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On 11/1/2018 at 2:46 PM, Journey said:

I'm sorry MVAF for your loss.

I absolutely agree with you, however, we can't do that as it would be detrimental the gene pool...

In collies that's true, but not in border collies where only 4-5% are carrying the MDR1 gene.  So in principle one does not want to heavily reduce the gene pool to eliminate a single genetic defect, but MDR1 -- which is cruel and highly limiting -- CAN be eliminated while retaining over 95% of border collies in the breeding pool.

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On 11/18/2018 at 8:42 PM, Amelia said:

I'm late to the party. Was directed here by a friend after she learned I had a Tanhill Glen daughter. I have not, but will have her tested for this mutation as a result of this thread.

....

Welcome to our sport, Mr. Drake. My strongest recommendation is to ignore the haters...

 

Your first comment @Amelia makes me wonder; was your breeder not informed of the genetic issues or did they neglect to tell you? I hope your test results are normal. I'd hope too after your comments here you'd post publicly the results.

The second comment I find completely unnecessary. No one hates Steve and your need to mention him directly I find odd. It's not his fault he wasn't made aware of the issues when he bought Glenn. One can only hope going forward he's open and honest with bitch owners who use Glenn.

TSDA has a great site. Anyone that wants to see trial results can simply go look them up. Last I saw there was 2 years worth of Glenn. He's not that "new" to the US. 

Coming a year now since I went to the HEF about MDR1, I've come to accept that nothing will be done for the most part. Sure, there is a verbage change on the website, beyond that, not much.

The annual newsletter had all the info about EOAD and the research progress but not a blip whatsoever about MDR1. Lost opportunity imo to inform the members of this situation. 

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I am working on this. It's a pretty complicated subject actually, and reading and properly evaluating the scientific literature as well as trying to find personal accounts in breeds other than border collies (where the incidence is extremely low) will take some time. Most of the dog forums and personal accounts revolve around heart worm medicine and other commonly used meds such as acepropazime. I'm just trying to be thorough because it's important. I'm sorry it's taking so long.

 

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Thank you @Denise Wall, I know you are working on this now. I just feel with the yearly newsletter a huge opportunity was lost to inform the membership that this genetic defect is in the United States. What @Eileen Stein placed on the heartworm pinned post I think is great! However, unless you're reading this thread no one would even know about mdr1 being here in this country. @Amelia  wasn't even aware of it until her puppy was 8 months old. How many others are out there now completely unaware? 

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I've recently come across this research/presentation. Not only is it bad for all dogs on HW/Flea medication, it's a double whammy for MDR1 dogs. I've spoken to a few people about this and their consensus is this is something we should carefully watch and research, scary... @betty boop dog lover, while this may not pertain to Hogan's nystagmus, it made me pause wrt his focusing issues, if he is MDR1. 

Just one more reason I feel something should be done to eradicate MDR1 from the breed, now.

 

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You do realize the dogs in “group 1” were given 33x (200mcg/kg) the effective minimum heartworm preventative dose (possibly in the range of ivermectin toxicosis)?

 

“Dogs that are homozygous for the mutation produce a severely truncated P-glycoprotein (<10% of the normal amino acid sequence) and will develop ivermectintoxicity at any of the dosages used to treat demodicosis. The critical point seems to be 120–150 mcg/kg, at which transient, nonfatal clinical signs (mydriasis, ataxia, tremors) are seen. At higher dosages, collapse, coma, and respiratory collapse may develop. Similar idiosyncratic reactions may develop in any breed, so a gradually increasing dose (daily progression of 50, 100, 150, 200, then 300 mcg/kg) should be given to identify susceptible individuals. Administration should be stopped if any adverse effects are seen.”

source: Merck Veterinary Manual

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1 hour ago, Mark Billadeau said:

You do realize the dogs in “group 1” were given 33x (200mcg/kg) the effective minimum heartworm preventative dose (possibly in the range of ivermectin toxicosis)?

No, where does it say that? I know he verbally corrected the info that was on the screen...wrt to dosages.

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Understand, so if their dosage is so incorrect would the takeaway be that there is nothing to worry about it all?

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The authors main conclusion was to avoid a 200mcg/kg dose and they reported on the side effects of such a high dose.

“High dose” will differ based upon the mdr1 genetic status of the dog.

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Ok, what about group 2 and 3? 

And would not an MDR1 dog be more susceptible due to the defect, just in general? Not just speaking of ivermectin.

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“High dose” will differ based upon the mdr1 genetic status of the dog.   =   The mdr1 genetic status of a dog will lower the dose of certain drugs where side effects can occur.

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One main concern of mine from this presentation is the possibility that Comfortis and Trifexis (popular flea and tick preventatives) are inhibitors of p-glycoprotein, the protein produced by the MDR1 gene, and as such can increase ivermectin concentration 360%. See the slide at 59 seconds of the video. If true, this is concerning for all dogs on heart worm prevention. I think it's something that bears following.

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Denise, my biology is not good enough to understand “direct GABAergic effect”.  What does this mean and will it alter the effective dose of ivermectin (and other heart worm preventatives)?

 

l’m trying to determine if the combination of ivermectin and the flea and tick meds in the Group 2 dogs make the side effects observed in this group similar to the Group 1 dogs getting 200mcg/kg.

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This study measured the plasma concentration of ivermectin and fluralaner after dosing with just one drug and after dosing with both.  There was no interaction between these drugs altering the plasma levels as is the case with spinosad  increasing ivermectin plasma concentrations as noted by Denise (quoted below from larger background section in this study).

https://parasitesandvectors.biomedcentral.com/articles/10.1186/s13071-015-1123-8

Ivermectin is registered for the use in dogs at monthly oral doses of 6 mcg/kg BW for heartworm protection [8]; some veterinarians may choose to administer ivermectin at higher off label doses to treat dogs for different worm or mite infestations (for example 0.05 mg/kg for hookworm, 0.1 mg/kg BW for whipworms, 0.2 mg/kg for Toxocara canis, 0.2-0.4 mg/kg for sarcoptic mange, 0.2 mg/kg for nasal mites Pneumonyssus caninum, 0.3 mg/kg for cheyletiellosis, 0.3–0.6 mg/kg for demodicosis; orally or subcutaneous as single or repeated treatments) [91011121314151617181920]; however, such high doses of ivermectin cannot safely be administered to “ivermectin-sensitive” dogs carrying a MDR1 mutation [2122]. Ivermectin is a substrate for the p-glycoprotein (p-gp) transporter encoded by the MDR1 gene [2223]. This transporter limits the entry of its substrates into the body by an efflux-based mechanism, particularly at the blood–brain barrier [24]. Dogs with a homozygous defect of the MDR1 gene do not carry a functional p-glycoprotein transporter and are therefore more susceptible to neurotoxicity caused by ivermectin [21]. Furthermore, drug-drug interactions at the p-glycoprotein transporter may occur following the concurrent use of ivermectin and drugs, leading to an increased risk of neurotoxicity of ivermectin in MDR1 intact dogs. One example is spinosad that inhibits the p-glycoprotein transporter-mediated elimination of ivermectin in MDR1 intact dogs, thereby increasing ivermectin blood concentrations, which leads to a higher risk of neurotoxicity when administering high off-label doses of ivermectin concurrently with spinosad [252627282930].”

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I finally got a chance to go through this video again trying to pay more attention to detail. Basically, my take on it is, as is obvious, it's not good to use high dose ivermectin (group 1). Lots of problems. In group 2, these dogs, different breeds and with their MDR1 status unknown, were already suspected of having retinal problems in association with regular heart worm meds alone or in association with other flea and tick products. Group 3 contains a "pure" group of dogs taking only regular dose HW meds but again, no info about the breeds or other info such as HDR1 status of the dogs. Group 3 also contains a control group that took no HW product and consequently showed little retinal toxicity.

So group 2 that would be most dogs as far as their mix of various HW, flea and tick products. But it's not exactly a pure group since they were already suspected to have retinal toxicity in association with HW/flea/tick products. As would be expected, this group did have various positive signs of retinal toxicity, some of it reversible once removed from the meds.

Group 3 (non control) was the most disturbing to me with about 21% of dogs showed retinal abnormalities. This is the group I don't know what to think about. This was just regular dose HW med.

I think there is evidence that there can be retinal problems with ivermectin/heart worm meds either alone or in combination with certain flea and tick products. Retinal problems may not be the only problems either. However, we really don't know much about which dogs, which breeds and whether the dogs had other problems contributing to these problems in this study at least. I suspect this could involve MDR1 as it's a likely suspect but more research is needed. There are genes that regulate production of the protein the MDR1 gene produces that could be a major factor for example. 

As someone who's been in the literature on this topic a fair amount lately I have to say it's amazing to me how little research has been done on this pretty important gene product in dogs. Especially given the number of breeds with high rates of mutation in this gene. Perhaps studies like the one in this video will lead the way to more sophisticated ones with more answers and better guidelines and better products.

So that's my follow up on the video. I hope I didn't miss anything. 

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Denise, thank you! Thank you so much for the article in the newsletter! Very much appreciated!

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Just circling back around to this after the wonderful write up Denise did in the newsletter. Curious, is there any chance of getting the website updated to reflect what was written in the annual newsletter?

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