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Pharmacogenetics: Gene-ius Solutions for Safer Anesthesia in Pets with Dr. Tania Perez Jimenez
437 Plays2 months ago
We here at NAVAS are excited to bring you a new podcast episode for the new year! And we're starting out our season of the NAVAS podcast with engaging exploration of pharmacogenetics, a groundbreaking field that examines how the genetic makeup of an animal can influence its response to medications.
Have you ever had a dog or a cat that took hours, if not days, to finally return to normal after general anesthesia? It's possible that animal had a genetic mutation that altered its metabolic function, causing profound changes in the clinical effects of anesthetic drugs.
In this episode, we are joined by veterinary anesthesiologist and overall gene-ius Dr. Tania Perez Jimenez, Assistant Professor of Anesthesia at Washington State University College of Veterinary Medication and head its Pharmacogenetics Laboratory. Dr. Perez Jimenez shares her expertise on the genetic factors that impact anesthesia and pain management in dogs and cats. Together with host, Dr. Bonnie Gatson, they will discuss how genetic variations can affect drug efficacy and safety in individual animals, how you can approach anesthetic management in dog breeds that commonly manifest genetic anomalies such as MDR1 mutations, why we may need to alter the way we utilize Propofol and Alfaxalone in cats and certain dog breeds, and how we could all benefit from going to more cat shows.
Explore more information discussed on this podcast at the WSU Pharmacogenetics Laboratory website.
If you like what you hear, we have a couple of favors to ask of you:
Become a member of NAVAS for access to more anesthesia and analgesia educational and RACE-approved CE content.
Spread the word. Share our podcast on your socials or a discussion forum. That would really help us achieve our mission: Reduce mortality and morbidity in veterinary patients undergoing sedation, anesthesia, and analgesia through high-quality, peer-reviewed education.
Thank you to our sponsor, Dechra - learn more about the pharmaceutical products Dechra has to offer veterinary professionals, such as Zenalpha.
If you have questions about this episode or want to suggest topics for future episodes, reach out to the producers at education@mynavas.org.
All opinions stated by the host and their guests are theirs alone and do not represent the thoughts or opinions of any corporation, university, or other business or governmental entity.
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Transcript
Introduction and Podcast Overview
00:00:06
Speaker
Hello, gas passers. Welcome to a new episode of the North American Veterinary Anesthesia Society podcast, the show where we explore the fascinating world of veterinary anesthesia and pain management. Our goal with this podcast is to advance and improve the safe administration of anesthesia and analgesia to all animals.
00:00:26
Speaker
I'm your host, Dr. Bonnie Gatson.
Focus on Pharmacogenetics
00:00:29
Speaker
As you may have noticed, especially if you are an observant, an avid gas passer, we skipped our monthly episode last month, and we have decided to start anew with the new year. I guess I decided that after two years of producing episodes on a monthly basis, I could just allow myself to just take one month off.
00:00:53
Speaker
But now we are back, and in this episode, we're diving into a cutting-edge topic that's shaping the future of personalized medicine for our furry patients, pharmacogenetics.
Sponsorship Acknowledgment and Membership Benefits
00:01:05
Speaker
But before we get started, we need to thank the sponsor of this podcast, DECRA. Not only do they help us at the NavVis podcast to provide continuing education to all you gas pastors with these monthly episodes,
00:01:19
Speaker
but they also provide a range of high quality anesthesia related products. To check them out, please visit w www-us s dot.com. Also, if you're not yet a member of the North American Veterinary Anesthesia Society, make it your new year's resolution to join.
Genetic Influence on Drug Response
00:01:40
Speaker
NAVAS membership comes with a range of benefits, including access to continuing education events, focused on anesthesia and pain management,
00:01:50
Speaker
informative blog posts, fireside chats with board certified anesthesiologists and specialty technicians, and just so much more. With the fireside chats, members can join virtual discussions where you'll have the chance to share your insights or ask a pressing question directly to experts in the field. If one of your New Year's goals is to increase your veterinary anesthesia knowledge, visit www.mynavas.org to take your anesthesia expertise to the next level. So back to the episode for today. Have you ever had a dog that took hours, if not days, to finally return to normal function after being sedated?
00:02:35
Speaker
Maybe you've heard something about red-headed people needing more anesthesia to achieve the same level of pain relief or sedation as people with other hair colors. Could this also be true for dog breeds with different coat colors? All this circles back to pharmacogenetics.
Guest Introduction: Dr. Tanya Perez Jimenez
00:02:55
Speaker
Pharmacogenetics is the study of how an individual's genetic makeup influences their response to medications. And since sedation and general anesthesia typically involves careful titration of several drugs that may profoundly impact our patient's physiology and homeostasis, it's very likely that our patient's individual genetic makeup may significantly impact their response to anesthetic drugs.
00:03:22
Speaker
While it's a concept that's gaining traction in human medicine, it's equally critical for understanding and improving anesthesia and pain management in veterinary patients. How can genetic differences impact the safety and efficacy of anesthetic drugs in dogs and cats? What role does genetic polymorphism play in determining how animals metabolize and respond to analgesics?
00:03:48
Speaker
And perhaps most importantly, what's the difference between a heterozygote, a homozygote, and what was that I just said about genetic polymorphism? To help us unpack these questions, we're thrilled to be joined by Dr. Tanya Perez Jimenez, an assistant professor of anesthesia at Washington State University College of Veterinary Medicine. Dr. Perez Jimenez also oversees the pharmacogenetics laboratory at WSU, where her research focuses on the intersection of genetics and veterinary pharmacology.
Crucial Role of Pharmacogenetics in Veterinary Medicine
00:04:20
Speaker
She brings us a wealth of knowledge and expertise to today's discussion, and we're excited to learn from this gene, yes.
00:04:28
Speaker
In this episode, we'll explore why pharmacogenetics is becoming an increasingly important consideration in veterinary medicine. We'll also discuss how variations in DNA sequences can influence the anesthetic efficacy and the risk of adverse drug reactions in companion animals. And we'll spend some time focusing on a few specific pharmacogenes.
00:04:50
Speaker
By the time this conversation is over, we hope you'll have a deeper understanding of how genetic insights can transform the way we approach anesthesia and pain management for our patients.
Dr. Perez Jimenez's Background and Research Journey
00:05:01
Speaker
So let's get started.
00:05:07
Speaker
Hi, welcome to the NavVis podcast. Thank you so much for agreeing to be on and speaking with me today. Can you start by introducing yourself and just briefly describing your past training, your current role, and what draws you into being interested in this particular field of study? Hello, Bonnie. Hello, everybody. Thank you for the invitation. Very happy to be here.
00:05:34
Speaker
Because it gives me a chance to talk about what I'm doing like right now and what I really like, which is the realm of pharmacogenetics. So who am I? My name is Tania Perez. I am a veterinarian from Colombia. I did my DVM in Colombia. And kind of after that, I kind of started traveling around the world a little bit. I went to Chile and did my master's degree in Chile. Then after that, came here to the US, Washington state, did my residency.
00:06:03
Speaker
and anesthesia and analgesia, so finish the residency. I went into a PhD program, which is pretty much where this whole thing started. So I was lucky enough, I should say that, to work with Dr. Michael Kord, which he's also a border anesthesiologist, but he dedicated his time after clinical practice to pharmacology. Okay. So I started working in his lab, did all my research, all my PhD in his lab, and then I got boarded.
00:06:33
Speaker
course in that time as well. So I got awarded and then I got hired here as so right now I'm an assistant professor here at Washington State University at the College of Admin. And I have additionally have continued my work in the same area which is pharmacogenetics. So that's a kind of a small rundown of what I've been doing in the past decade or so.
Clinical Observations and Genetic Variations
00:06:56
Speaker
Yeah. And I'm very excited to speak with you because we don't know each other personally. I think it's like the first time we're meeting each other. But when I was a resident, I went to one of the anesthesia conferences at IVEX. I remember listening to a presentation about differences in, I believe it was
00:07:17
Speaker
opioid consumption or it was pain scale pain scoring, um I think it was, or it was a max study, which honestly, now that I think about it, it's a lot of different options. But the question was, is there a difference in the experience that laboratory recruiters have as far as pain is concerned if they are like,
00:07:37
Speaker
a brown or a yellow or a black lab and I'm pretty sure that was your presentation and I think that was like the first time that I had really given a lot of thought to pharmacogenetics and I thought that presentation was like one of the most fascinating things I had heard in ah in a very long time. Okay I know what presentation you're referring to right now because at that time we did it wasn't a very big study it was actually like 30 dogs which It's not, it's vague. I mean, considering some of the studies that we do, and basically what we were trying to look at at that moment is what you're describing right now. And it's the difference in co-color. Yeah. Why the difference in co-color? Because we know as anesthesiologist that there are differences in anesthesia sensitivities in people that have different hair colors. And these came out obviously of the, you know, red headed women that need more anesthesia just because of their genetics.
00:08:36
Speaker
So we thought, and it has been proven in other species, that the difference in your coat color or your hair color determines a little bit of your response to certain, not just medications, but to certain stimulus, okay? And that is also related to the gene that actually gives you your hair color, which is the monocortin-1 receptor. And that's the presentation that you went to. And that's what we did at the time. So basically what we did is we grabbed 10 yellows, 10 chocolate, and 10 black lambs. And we did find a little bit of an association. It was a little bit of statistically significant, but for 30 dogs, we thought it was actually pretty cool because we could see a difference between the yellows and everybody else. Your comment is important for what reason? And this is kind of what led to the discovery of a lot of the things that we know right now, which is clinical.
00:09:34
Speaker
anecdotal evidence, okay? So a lot of these things we see them in the clinics, okay? So we get the typical yellow lab that is bouncing off the walls, right? That we give them drugs and then they wake up like everybody can hear them on the other side of the clinic, correct? And there are certain things that we observe in the clinics and we're like, is it just because he's young or is it just because what we did is painful or is it because of the breed relationship?
00:10:03
Speaker
And that's where that study came off of Bonnie, basically. And they have done it in chickens. They have done it in different like horse co-colors. And definitely, why is there a difference? What does the color of your hair has to do with that? And the connection is that the melanocortinone receptor is actually located in some of the pain pathways. So the connection comes from actually there.
Pharmacogenetics and Drug Administration
00:10:28
Speaker
So the change in your sensitivity comes up because of where this receptor is also located.
00:10:33
Speaker
So it also, it only doesn't just give you your hair color. It also participates in some of the pay pathways. So let's jump into that. That was like a little taste of where we're going to go from here. And so, yeah, let's jump into the pharmacogenetics world. And let's start by that by talking about what pharmacogenetics is and at least how it pertains to veterinary medicine. Of course. So it looks like a big word.
00:11:03
Speaker
but when you when you analyze the word, right, pharmacogenetics is basically the association between your genes and the response you will have to a specific medication. That is basically what that means. So what we do in in in pharmacogenetic studies is we basically, we're trying to find if there is a change or if there is a mutation or if there is anything that is affecting you're not just metabolizing enzymes, because obviously they are very important, metabolizing enzymes. And what I'm referring to most specifically is going to be your cytokine P450 enzymes. That's where most of the work has actually been done. But it's not just that. It's not just only how you metabolize the medication, but it's also how you transport a medication and how you eliminate it from some places. So now that I've said that, some of you are gonna go, oh my God, oh my God, yes, the MDR1 gene.
00:12:01
Speaker
Yes, you are absolutely correct. The MDR1 gene is basically the BIP, what we call the BIP of the pharmacogenes, because it it wasn't not just only one of the first ones, but it's one of the ones that have been most more studied in the literature, right? Why is it a pharmacogenes? And why do we call them pharmacogenes? It's because the genes that encode for the protein that creates the enzyme or the receptor or the transporter, right?
00:12:30
Speaker
the gene is altered in some way, shape or form, okay? It could be a mutation, it could be a deletion, it could be a stop codon, you know, like typical things that will damage, not just how the protein is synthesized, but the protein function, per se, as well, could be affected. And that's kind of what happens with the MDR1 mutation, for example. There is a stop codon in a specific part, and then the protein gets completely truncated, and that's it. Doesn't work anymore, doesn't do anything, okay? Doesn't do anything.
00:13:00
Speaker
How did we find this out? What we were just talking about. Clinical observance. When we were a servant in the clinics, you know, these patients were given these medications. And as you all know, as we all know, right, this started with avermectin. Right. So, the lactic, microcytolactins. Started with avermectin. They gave avermectin to these dogs, and these dogs were just going to come and die, okay? So everybody's like, okay, well, why is it only the colleagues? And that's when the whole thing just actually
Need for Breed-Specific Studies
00:13:26
Speaker
came about. Obviously, he it's not only the colleagues. There are more breeds.
00:13:30
Speaker
but unfortunately, up to 70% of colleagues can have this mutation, okay? Can have this mutation. And that's unfortunate not unfortunate, but it's a really good example of when you pay attention in the clinics and you see something, it pays out. We have a pretty good idea if you took like a sample size of a bunch of healthy beagle dogs and you ran like a pharmacokinetic study of those dogs, then we get this information that comes back to us about how that drug kind of moves around the body and how it's eliminated from the body. What I'm hearing from you is that there are populations of animals out there that have genetic mutations associated with these pharmacokinetic principles that then alters the way either that drug is transported around the body or metabolized or eliminated and that results in a different
00:14:23
Speaker
pharmacodynamic presentation. Is that correct? That is absolutely correct. That's the cool thing about pharmacogenetics, because pharmacogenetics is directly related to pharmacokinetics and pharmacodynamics. And a lot of the explanations that you find in the literature are specifically related to how it affects absorption, distribution, metabolism, and elimination of drugs. And you can find pharmacogenes all along those different parts of the pharmacokinetic process. What is the end goal?
00:14:52
Speaker
You know, because everybody said, yeah, well, pharmacokinetics, but what? Well, the principles of pharmacokinetics is basically creating a safe way to administer medications, finding the safety and the efficacy of that drug for that population so that doesn't happen again. So what we're aiming for is making it safe, because that's what, for example, the MDR1 mutation has done.
00:15:20
Speaker
that basically tells you you have a colleague, don't give it this, don't give it that, even if you don't have the genetic background of the dog, even if you don't have it. So it's not completely necessary for you to, okay, but I don't have the test. It doesn't matter, but you have information that tells you, be very careful with this dog and be very careful with these drugs because you don't know. And that has helped a lot of people, for example, make decision as to about how do I deal with this patient if a colleague comes in, but I don't know their MDR1 status. Yeah, I think you've made a really good point about
00:15:58
Speaker
how we could utilize the research that's coming out from this field, at least in a clinical setting. My other question though, is what areas do you think we need more information about so that we can make good clinical judgments about animals that we have a high suspicion have certain types of pharmo genes that can affect them clinically? I mean, that is an excellent question, Bonnie. It's an excellent question mi because At least what you can see from the from the literature that's available and and you know the things that I've read and some of the research that I have personally done, it will be ideal for us in the veterinary medical field to be able to be more selective when it comes to specific breeds. Because we do know, at least from the small numbers that we have in the literature, and now those numbers have become a little bit bigger as the time goes by, but we know that there are breeds that are different than others. Now we know for a fact.
00:16:58
Speaker
Okay. In all kinds of medications, not just anesthesia medications, but all all the kinds of medications. And we know that there are breeds that are particular. We know that there are breeds that are more sensitive. We know that there are breeds more resistant to it. And I think we need more studies in those specific breeds to kind of figure out if there is anything else there. The reason why I bring this up is because you actually brought it up and you talked about the videos. Yeah. Okay.
00:17:27
Speaker
The beagles are special, and they're not just special because, you know, they are special but because they have their, and why are we so interested in beagles? so Beagles, as you know, are the, or were, or still are in some places, the breed that is the predilection for pharmacological studies, okay? They do those pharmacological studies in the beagles to gain information for human drug development, right?
00:17:57
Speaker
Well, what they're not doing is using that information to help us.
Statistical Modeling in Pharmacokinetics
00:18:02
Speaker
And the reason why I bring this up is because of what happened with selective. Okay. So the coffee was big in the nineties. Okay. Was a Cox, you know, so Cox too selective. And then they did this study of about 250 dogs at that time, which is a pretty decent amount of dogs. And they were all beagles. Okay.
00:18:21
Speaker
So basically, they were trying to gain you know the the use of the medication for humans and all all this kind of stuff. And what they noticed in this study is, first of all, they noticed that there were some changes in the enzyme. And that enzyme is C2D15, which is the enzyme that I'm studying right now. And they found that half of the population, half of those vehicles metabolized the drug really fast.
00:18:46
Speaker
Like we're talking fast, but does that mean that if I give you this medication and you metabolize it and you eliminate it really fast, then you have no therapeutic advantage of the drug because the drug disappears so fast that your analgesia only lasted you four hours. Let's say this is an example and know the 12 that is supposed to be correct. Then you have the opposite, which the other half of the beagles were actually very poor. So we're not able to metabolize the drug.
00:19:16
Speaker
What does that mean? We have an NSAID that is going around no being able to be metabolized. What are going to be your side effects from it? What is your kidney going to do, right? What is your liver going to do? So like COXIF stayed on the market for a little while and it disappeared, okay? And one of the reasons why we believe is because of this information that we now have. Why is that important? Because it was beagles. So now we know that beagles have mutations on this enzyme that could make them prone to have issues with COX-2 selective medications.
00:19:51
Speaker
so first of all i didn't know that information about beagles so i just learned something but the other thing that i'm hearing from you is that need to change at least for veterinary medicine the way we're doing pharmacocontic studies in kind of like two big ways which is like we need more Advanced statistical modeling to look at like population pharmacokinetics across like the entire population But then also we might need like more breed specific Pharmacokinetic data yeah as well and maybe we could be selective about the breeds were picking based off of what as a community we are observing more commonly
MDR1 Gene's Role in Drug Safety
00:20:30
Speaker
and Yes. And I think this also leads to, you know, another big can of worms. We talk about widespread event monitoring, meaning like if there's an adverse event that is documented in the veterinary community, it would be like so amazing to be able to have a place where you can like report this. I absolutely completely agree with you because another problem that I see, and this is this is me because of the things that I've done.
00:20:58
Speaker
this past couple of years is that there is not databases that are not just selected, but there are the streamline in a way. Okay. And they're not standardized. That's the word I was looking for. They're not standardized. So if we don't have anything that is standardized,
00:21:13
Speaker
how are we going to be able to analyze these data? Right. Well, let's jump into what we do know, even though not very much. And we're going to talk about a few specific pharmacogenes that specifically affect anesthesia and pain management yeah for our companion animal species. So I think arguably the most well-known gene that can alter our approach to clinical patients, as you've already mentioned, is going to be the MDR1 gene. Right. Although I have heard it has been renamed to ABCB1. Yes. Is that true? That is absolutely correct. Okay. So why don't we start with talking about what this gene encodes and how it can be altered in some patients.
00:22:00
Speaker
So the ABCB1, as you call it because they changed the name, they've changed that a little bit, but it's basically encoding for a protein that is called the P1 glycoprotein. Okay. So P glycoprotein is what we know as an IFLUX protein. What does that mean? IFLUX is basically taken out of. So this protein is located in a couple of different parts or a couple of different organs, right? As we should say.
00:22:30
Speaker
which are in charge of taking things out of the organ. The main one and the one we know most of, obviously, is the brain because of what we know of the evermectin and the colis. It's the brain. But this protein is also located in the kidney. It's also located in the intestines. And it's additionally located in the liver. So it's helping take the medication out of these organs to be eliminated and, you know, all these absolute things.
00:22:59
Speaker
But the protein is key in the brain and
Drugs Affected by MDR1 Mutation
00:23:02
Speaker
why it has been more importantly like research in the brain is because the drugs, once they enter the brain, they can't get out. Okay? And the drug basically just gets stuck in the brain. So it crosses through all their mechanisms, right? And then when it needs to be ejected from the brain, it cannot because the protein is nonfunctional, right? So it might be there, but it's just not functioning at all. Okay, so they have done and the really cool studies where they have seen the difference, for example, between a patient that is normal, or what we call a wild type. And what is a wild type? What are you talking about wild types?
00:23:46
Speaker
Biotype is basically what you know also as a phenotype. And I don't think we have talked about that. We have talked about genomes, and that's known as a genotype. So you're goingnna you're going to have a specific genotype for that, but you're also going to have a specific phenotype. What does that even mean? Well, basically, the phenotype is telling you if you're normal, right? If you're somewhere in between, and that will be the heterozygous, or if you're a mutant, right?
00:24:13
Speaker
That's basically what those phenotypes mean. So it's telling you you're normal, you're wild type, you're a heterozygous, you have one good one and a bad one. And that's all related to the amount of genes that you have. And remember, we get one gene from mom, one gene from dad, right? So everything in the body is based exactly the same way. So you have two genes and they both should be working fine and should be normal. That will be your wild type, okay? And then you have your heterozygous which is like, oh, you got 50-50. See? You got basically half that is okay and the half that is not okay. And then you got your mutants, which are the ones that have nothing. yeah Okay? The ones that have basically nothing. And those are the dogs that we should really be concerned about. That being said, we need to be very careful because the heterozygous can also have a little bit of an adverse reaction to these medications. So even if you have a half of a copy,
00:25:10
Speaker
you are is still likely to have some kind of a reaction. It could be not as severe as the one that doesn't have anything, which is a mutant, but it could be significant. So we also worry about those dogs particularly. So then the medication comes into the brain, but then it can't get up. So that's where the side effects of all the things that we know started happening with MDR1. So you're talking about people like a protein. Why is that important for us? Anesthesiologist, okay?
00:25:39
Speaker
mi because A lot of the medications, and not a lot, I think this is good for us, is because only a few medications that we use are actually transported through this Graco protein. Which ones are those, you would say? Okay, the ones that I have knowledge from the literature and the research is Ace Promethin and Butorphanol as our pre-medication and our analgesics.
00:26:03
Speaker
and then serenia and also gallibrant. Those four, at least that we have information backed up by the literature that we know, for example, that the patients that are mutant or heterozygous, their recommendations are either to avoid the medications or to decrease the dosage of the medication and observe the patient. So that what goes back to the recommendation that I was making before. If you don't know, okay, and for example,
00:26:32
Speaker
We all know what it's from, as you can do, okay? And we all know that even in a healthy patient that has no problems, the sedation can last a little longer, okay? Couple of hours, it's really long, it has no reversal agent. But what happens with a patient that has this mutation? What we know from the literature, and you probably have heard this, it takes them really, really, really long time to recover. And the reason why it's taken them so a long time is because the medication cannot be ejected from the brain. So it's doing its effects because it just can't get out.
00:27:03
Speaker
Could it be a problem for a patient? Of course it could. Definitely. Could be a significant problem. So that's where those are recommendations come from. And if you log on, for example, into our pharmacology laboratory webpage, the the list of all the drugs are there. And some of them have specific recommendations for use. They tell you decrease 25%, do not give.
Opioid Use in MDR1 Mutation Cases
00:27:26
Speaker
And for, for example, for Serenia and Galliprant,
00:27:29
Speaker
they tell you to communicate with the laboratory for our recommendation about dosing. I think most people's experience with dogs that have a mutation for the ABCB1 gene, I think most people jump to like ace-promazine because there are very nice studies out there that do show that these dogs have prolonged sedation with ace-promazine.
00:27:48
Speaker
Personally, when I practice, I just don't use Ace Promazine in this particular breed at all. But the other are these breeds where there's a high propensity for the mutation. I just don't use Ace Promazine. Correct. The other thing I just want to point out from my personal experience that if you do use Ace Promazine as a pre-medication because it's part of your anesthesia protocol. And you have that one dog that just like the owner reports it slept for like two days or just was like a little dumpy for two days. This is a great time to talk about MDR1 with the client because it's possible that if you had an animal that had ah like ah an abnormal response, particularly that drug, that's like the first thing I'm recommending to people.
00:28:34
Speaker
The second question that I get asked a lot, at least when it comes to medications that we use as anesthesiologists and this particular mutation has to do with opioids. yes And if we should avoid opioids in animals that have this particular mutation, and this is my recommendation, but i I would like to hear yours. Maybe it's different from mine, but I don't necessarily change the way that I utilize opioids with these animals, particularly if they're having some kind of painful procedure done or they have a painful condition going on and the big reason why is because these drugs are reversible, have naloxone and it's still antagonize the drug.
00:29:20
Speaker
And, you know, maybe I will aid on the side of caution and use a lower dose at first or titrate to effect. Maybe I will use a CRI so that I can titrate it. Maybe I'll use a drug like Remu Fentanyl, for example, if I've access to that. That might be a great option for these animals, but I do not avoid using opioids really at all in these animals. And I'm wondering if that is your experience too.
00:29:47
Speaker
I think you're absolutely correct in everything you just said. Oh, hooray, I love that. Because this is exactly the same thing I do, okay? Now, I have a question about serenia because I think this is like a new one that's coming out and people, not that it's new, but just like it's kind of coming through the grapevine. I'm getting asked more questions about should I avoid serenia in animals that have this particular mutation?
00:30:15
Speaker
And to be honest, I usually still recommend using serenia, especially if you're just using it for like a single dose. If you're going to be putting the animal on, you know, like five days of serenia, you know, maybe ah I would change my mind about that.
Drug Recommendations for MDR1 Mutation
00:30:32
Speaker
But my understanding of it is it doesn't necessarily have to do with the P-like or protein effect in the brain so much as it has to do with like in its effect in the liver.
00:30:41
Speaker
And so it might just take a little longer to get metabolized. So I still use, I personally still use the same dose. I just use it like once. Yes. and i't I don't know if that's what you do. Correct again. Correct again. Yeah, yeah <unk> exactly right. So the thing with Serenia, it is, we know it's an NK antagonist, but also it doesn't really cause CNS depression, which is the main concern, obviously with the medications that are substrates for ABCV1. But the main concern actually comes on is from the prolonged duration of use, like you just mentioned, particularly. The five days that is recommended according to the the manufacturer, right? So the recommended five days. Another thing that you're going to see starts happening, not just because of the efflux of the medication, but is the saturation of the metabolic processes. Because C2D15 is the one that actually metabolizes this drug, so you have another issue right there, and it does get
00:31:39
Speaker
after the five days, it gets to a specific saturation and the enzyme cannot metabolize the medication anymore. That's where that recommendation of five days actually comes from. Yeah, there is a little bit of relation of picolycoprotein and how it goes into the brain. And actually I have talked to this with the pharmacology lab and I've asked them, what is your recommendation? What are you telling people to do when they call you? Basically what they're saying is,
00:32:06
Speaker
One of the recommendations they're making is just to decrease the dose in about 25%. Interesting, okay. Yeah, that's one of the things that mostly they're, and the same thing goes with the Galliprent, for example. Yeah. Galliprent, they're making actually the same recommendation. And the one with Galliprent, if I may, just say a little bit about Galliprent, even though it's not something we use a lot, but a lot of people that do pain clinics, they use it for chronic pain management. You know, when your patients are sensitive to NSAIDs and the thing,
00:32:35
Speaker
And, uh, the paper actually that they wrote related to specific needle gallop print. The biggest concern was the side effects that the gallop print was generating, which is basically GI. Yeah. So it comes back again to the P glycoprotein patients that are mutant or Hithers hygus to it, and how likely they are to develop GI. So vomit, diarrhea, and it was more likely a mutant dog to develop it than a dog that was a wild So I just want to bring that out so people are oh cognizant of what is happening to the patient. And if we're more likely to see GI disturbances, okay? So if you see that and your patient is not tested,
00:33:17
Speaker
I will highly recommend that to get your pet tested for MDR1. The other question I wanted to ask is about breed types that are represented. I think the classic is like Collie's, as you mentioned, those dogs, I think about 70% have some type of mutation. I don't know if that's a full mutant or heterozygote. What other breeds of dogs do we know have a high prevalence of this particular mutation?
00:33:46
Speaker
That is actually a great question, Bonnie, because actually we do know which breeds and these encompasses not just the mutants, but also the heterozygous. Yeah. Okay. So we know that in the colony population is over 70% of the colonies. Be very careful additionally with your ah Australian shepherds, which is about 50%. And this also encompasses your miniosis. Yes. Okay. So miniosis,
00:34:16
Speaker
or Australian full-grown or Australian shepherd, about 50% of them are likely to have the mutation. And then there is a couple of other breeds that are pretty high, and one of them is the whippet. I always forget about the whippets. Yeah, don't forget about the whippets. The whippets are up there. And then there is a couple of of the sidehounds.
00:34:34
Speaker
Mm hmm. That also related to this. So the high the side hounds, poor things have problems in multiple. I know I was about to say, they have multiple fronts. And then the long hair is particularly the long hair weapon. Look at this how particular this is, right?
00:34:51
Speaker
So it's not just the regular whippet, but it's the whippet we loan here. And it's about 50% of them. What about border collies? You'll be surprised, less than 5% of border collies. Yeah, i be the only reason I ask about border collies is because you're always told like, white feet don't treat. That was the literal little, like, miles and vet school that was like the literal state. No, border collies, less than 5% of border collies are actually ah affected by the MDR1 mutation. Oh, that's so interesting. I know. Isn't it crazy? But look
Breeds with MDR1 Mutation Prevalence
00:35:22
Speaker
at this. I don't know if you've ever seen a silken one wind hound. Yes. ah About 30% of silken wind hounds are affected by the mutation. And there is a couple of breeds that I've never heard before that are also up in there. One of them is the McNab. I've never seen a McNab. About 30% of McNabs and Chinooks.
00:35:42
Speaker
Oh, I have to Google about those breeds. Google them. If you look at them, you're like, that was not a pure bred dog. They are. They definitely are. And then you start going down into like the Sheatland Sheepdogs and the German Shepherds. German Shepherds, about 10% of them. Wow. Yeah. i know And the Sheatland Sheepdogs is about 15%. And then all the breeds that are like Less than that, it will be the butterflies, which is about five, and then the old English sheepdogs, about 5% of them. Okay. Also, so there are some breeds that you need to be careful. And there are the other thing that we also need to be cautious is anything that has been crossed with a herding breed. Because this is where some of the heathers I guess can come from. But also if your dog has a herding breed in it, I will test
Drug Metabolism Proteins and Anesthesia
00:36:35
Speaker
it. Interesting. Because we know that also the breeds
00:36:39
Speaker
Also, the crosses can manifest in mutation. Yeah, maybe this is a sign for people who are in clinical practice. Yep. It's become very, and I would say trendy for people to get their dog like genetically tested to figure out like what breeds of dog yeah they are. And so maybe this is information that we should be asking our clients about yeah because if there is any amount of herding breed in their genealogy, that might be an interesting thing to know. Yes, absolutely correct. And this is what we have seen from the DNA bank that we have collected through the years here has helped us gather that information. Let's move on to a different set of pharmacogenes that are related to drug metabolism. Let's do it. So can you describe a little bit the role of what these drug metabolism proteins play?
00:37:35
Speaker
and how alterations in these proteins, which are obviously coded by genes, can affect both anesthesia and pain management. Basically, ah the metabolizing enzymes, okay, are an important part of drug metabolism, right? So the way they kind of done this is divided into phase one and phase two, okay? So the phase one, the biggest representatives are the oxidation processes, which is done by cytokine P450s. Why are they important? Because everything that goes into our body and everything that is producing our body is somewhat metabolized by these enzymes. Even endogenous products, exogenous things, you know, medications, even contaminants and pollutants that go into our body are metabolized and eliminated by these drugs,
Role of Cytochrome P450 in Drug Metabolism
00:38:24
Speaker
okay? So that's why they are so important. And that's the reason why they have been studied so much in even in human medicine, right?
00:38:30
Speaker
So if we know this and we go, okay, so on phase one, we're paying a specific attention to the cytochrome bifurcates. In phase two, we're paying a specific attention to glucuronidation processes. So to the UGTs, right? So the UGTs. Why is that important? Because of the cats. she Because of the cats and the issues they have with UGTs. And that's a pharmacogen that kind of went hidden for a little while. And then after it was discovered, the acetaminophen link, it just blew up.
00:39:00
Speaker
in our kitties. And we have so much information about the cats because of that mutation they have. And it's not really a mutation. The gene just doesn't exist. It's a pseudodule. So it's just not even there. It doesn't do anything. It's not even there. So then now we know why cats respond different to some other things than dogs do. And it's due to that. It's due to a lot of the medications that we use are glucuronidated.
00:39:26
Speaker
in high amounts, and I'm going to just take a side way to the cat so we cannot leave that out. So propofol, the NSAIDs, some antibiotics, medications that are heavily glucuronidated, and we have seen this in the clinics, why some dogs develop toxicity after one dose, some cats, sorry, develop toxicity after one dose, and develop whatever something or other with the propofol. Some people are afraid of using propofol in cats. Well, there is explanation for that, okay?
00:39:55
Speaker
and we know what the explanation is now, thankfully, okay? So that's the cool thing about that. And then the focus on the cytochrome P450 is particularly for anesthesia and particularly for the one that I'm studying, which is CYP2D15 is because some of our anesthetics, but mostly some of our analgesics are metabolized by CYP2D15, okay? And that's kind of like the whole thing started because it started with what is happening with tramadol, right?
00:40:23
Speaker
So just going back a little bit to how I got into this is because I did my PhD based on terminal metabolism, okay? Because I wanted to see what's the deal with it? Why yeah people say it works and why do people say it doesn't work? Well, we have found some connections in between that. And what is the other important pharmacogen? Which is seep to be 11. And I think for anesthesia, per se, that's probably at the top of the list. okay Why seep to be 11?
00:40:53
Speaker
it could seem to be 11 metabolizes propofol, alphaxin, and ketamine. Yeah, that's a big one. So ketamine also goes through that route. So when we look at it, we're like, okay, well, propofol, we use it every day, alphaxin, I don't know, you use it, we use it often, right? I use it like every single day. Every single day. And then we have ketamine, right? Also used every single day. Also used every single day. So then for anesthesia, per se, that's the pharmacogen that I will pay most attention to.
Glucuronidation Deficiencies in Cats
00:41:25
Speaker
Okay? What's the other cool thing about this pharmacogen in particular? It seems to be 11. It's going back to her greyhound population. It's going back to her sidehound friends. The association with the sidehounds, again, we saw this clinically, right?
00:41:40
Speaker
We will give thiopental, for example, which I don't know if you got a chance to use thiopental. I did. That was a long time ago. I only used thiopental once when I was a veterinary student, and I never used it again. Oh, there you go. So when I started practicing, which was a while ago, we still had it. And when I started my residency here in Washington State, we still had it. And I had a couple of cases. We used to know a couple of horses and some other things. But this is the interesting thing, right? We were anesthetized at Greyhound.
00:42:10
Speaker
The Greyhound wouldn't wake up, right? And we're like, oh my God, it took him so long to wake up. It's because he doesn't have any body fat. Hold on. There's got to be something else. And that something else was that, was that the Greyhounds and other members of the SIHAM population have a mutation in the gene. So that's why they cannot efficiently metabolize the medication and their recoveries are prolonged. Okay. Gotcha. So where do we come in as anesthesiologist in here?
00:42:39
Speaker
So the way we come in with this is if we get a side hound or any member of the side hound family, I'm going to go. Okay. Like you said at the beginning, I'm going to use this medication, but I'm going to use the lowest dose required for a specific purpose. I'm going to titrate to effect. I'm probably going to avoid doing a Tiva. Okay. Probably going to avoid that because I know the more I give this guy, the longer he's going to take to recover. Okay.
00:43:06
Speaker
And that's not ideal for a patient in this condition, correct? So I think that's where this also is super important one in some of the things on the points that you brought up that are key to this is that we do that based on this information. So if I get a sign on for anesthesia, I'm going to go, okay, I'm probably going to use probable, but I'm going to use the minimum dose available that I need for my purpose. I'm probably going to put him on inhalant.
00:43:30
Speaker
I'm not going to do a TIGA. I am going to do a balanced anesthesia protocol. I'm going to do good preemit, so I don't need a lot of probable, right? I'm going to do local regional anesthesia, so I decrease the amount of medications that I need. Ergo.
00:43:44
Speaker
patient safety. Because I feel like this particular conversation could be it's like own podcast. There's so much to be said about all of these proteins that you're mentioning. The big take home messages I'm hearing is you have to be careful with cats. They have a pseudogene yeah that does not properly code for one of the processes of like eliminating.
00:44:09
Speaker
many get yes yeah And so the prime example of that would be like acetaminophen. That drug undergoes a heavy amount of glucuronidation. So, you know, we don't use acetaminophen in cats because that can cause toxicity in that breed because they can't metabolize it properly. Correct. It's like one thing I'm hearing. The other thing I hear a lot about propofolon cats has to do with utilizing constant reinfusions or T.vas of propofolon cats.
00:44:40
Speaker
And, you know, I think the one thing I'll hear a lot of times is that we have to be careful about that because they can get Heinz body and anemia, which is outside of like what we're talking about with pharmacogenes. So it's not related, at least my under understanding is not related to pharmacogenes per se. But the other argument I have heard is that we want to avoid using Tiva with specifically propofol 28.
00:45:07
Speaker
Because ProBifold 28 has benzyl alcohol, and that is the preservative in that particular medication that allows it to have the long shelf life. And cats, because of their lack of appropriate glucuronidation, cannot break down the benzyl alcohol. Is that true? Because I feel like I've been in a pinch, personally.
00:45:29
Speaker
I've used propofol-28 repeatedly to keep a cat anositized. And you know the question is, does it go well or not? you know that's That's a really good question. I had a cat very recently that I was asked to consult on that was placed on a propofol-CRI because it was getting like a nasal workup and it was like getting extubated, re-intubated. So the the decision was made to utilize a CRI. And that cat like did not wake up from anesthesia.
00:45:59
Speaker
After that procedure and once they were able to activate the cat finally which was like hours and hours and hours later
Challenges with Anesthesia in Cats
00:46:07
Speaker
the cat actually wound up having several seizures oh and they had to basically feel like they had to do the whole shebang with the sea and the cat eventually did fine after two or three days.
00:46:19
Speaker
But there was just like, ah I mean, it's possible, their top differential is this cat had like an underlying neurologic issue or it had a vascular event, which is ah a completely reasonable differential to have, to be had. But there was like a part in the back of my brain where I was like, can I relate this or draw this back to pharmacogenes? Like, does this cat have a problem with you know, one of its CYP genes, and that's why this happens. But I was wondering, at least as far as cats with propofol CRI as a repetitive, repetitively giving propofol, do we have any information, if there's any practices that we need to alter based off of what we know about that so far? but Okay, no. What you bring is an absolutely excellent question. Okay. What you bring, no. And what you bring is is actually a question that
00:47:12
Speaker
we get asked often again and again and again, okay? And ah to go back to to your question, because of the Prop 428 and the Prop 4 with preservative and without preservative, I think the seminal study that was done by that, I think Dr. Robertson did that study a couple of years ago, or a decade ago, actually, where they did the study yeah with the cats with Prop 428 and the cats without the Prop 4, or with the regular Prop 4, you know, the one without preservative,
00:47:40
Speaker
And what we do know is that the one that with the preservative, which is the Propyl-28, and the benzyl alcohol, those actually contribute to some of the problems that we see, like the Haynes body anemia that you were describing, and the malaise that these cats developed, and how, you know, they choose ADR. You know, the kid is ADR, and the GI, and that they didn't want to eat, could be related to that, okay?
00:48:09
Speaker
definitely related to that, okay? The problem, and are not really the problem, is that when you look at propofol metabolism, okay? Propofol metabolism, more than 70% of propofol is actually glucuronidated. Now we know for a fact, yeah? And when that happens and propofol is severely glucuronidated, then you start thinking about, okay, if we know that about 70% is glucuronidated, what's happening with the rest? The rest, those are a couple of different things, And the rest either goes through cytochrome P450s, which we know what happens, which is about 30% of it goes through cytochrome P450. But interestingly enough, the metabolites of propofol get glucuronidated again.
00:48:54
Speaker
yeah So some of the metabolites of propofol goes through the cytochromes. So I think it's four hydroxypropofol. So four hydroxypropofol actually goes through multiple metabolic routes and gets glucuronidated again.
00:49:07
Speaker
So the poor cat is stuck with all of it. He's not just stuck with the propofol that can get out, but also the benzyl alcohol that can get out. Okay. So the poor cat is finding on all the ways to get rid of the medication and is believed because we don't really know this. It is believed that you either sent it through oxidation, which is hydrography for fifties, or you go through other phase one, which is sulfation. Yeah. That's what is believed that happens with The probable is obviously the clearing of the medication slows down and the half life of elimination is prolonged. So that's what's going on with the kitties. You know, to be completely honest with you, and this is, this is from me, when I have a cat and I have to do something very similar to what you did, because we do this all the time, you know, we have to do the scope and we have to do the bronchoscopy and we need to extubate and intubate. What are you going to do? Well, are you're going to do a Tiva obviously.
00:50:05
Speaker
I'm going to do propofol. What do I do? I usually tell medicine, you guys need to hurry. And we're going to do this CRI in this amount of time. If you're not done in this amount of time, we need to be very cautious because the kidneys recovery will be prolonged. Okay. And I've seen that happen, but not as long as you describe. Okay. I think that could also be an individual response because I have seen the cats take long.
00:50:33
Speaker
but I haven't seen a cap take this long. Yeah, the other thing I think that we tend to do with cats because it's just the way we're trained and like when we're trained on pharmacology, it's like we just group cats as like a big block, like cats, I'll do this. But if you look at like dogs, we're always talking about more subtlety, like the herding breed. Yes. and like this bit But you know, so many cats we see. are
00:51:04
Speaker
domestic short hair, you know, mixed breed things that all like five kilos, right? So I think it's so much easier for us to just like lump cats as a muck lift, but there's probably a lot of subtle individual variability that we just are like not talking about.
Practical Advice for Managing Anesthesia
00:51:26
Speaker
I agree with you a hundred percent in what you just said. I think you basically just hit hit the nail on the head.
00:51:34
Speaker
which is the cats. See, and the problem with with the cats is that we have domestic long hair. What what what does that mean? What does it mean? Genetically, what does it mean? Is it a mutt? Probably, okay. Because when we go look at cat breeds, it's not so widely known as dog breeds. Only the people that know about cat breeds is the people that show them. Cool thing at least about UGTs is that we know is across all cats. Yeah, that's kind of fast. So it's just the fact of being a cat that brings it on. So that helps some way. I know it doesn't explain everything, but the fact that you're a feline gives you this particular deficiency. Another comment that I was going to make now that you brought up the prop before is that I have seen what you were describing
00:52:26
Speaker
but I saw it in a cat in which we did an olfaxone xyra. Yeah, I actually am glad you brought that up. I wasn't even going to bring it up, but yeah I have like stopped clinically using olfaxone xyra in cats because I have seen in the, I mean, I haven't used it that much because I think I did it about five or six times and then decided I'm done with this, but I was seeing such a wide range of strange clinical signs that were happening in recovery. Honestly,
00:52:56
Speaker
regardless of the duration that I had the alphaxolone going. And I was seeing things like very rough recoveries, which is well-documented with alphaxolone, but also almost seizure-like seizurelike type of behaviors where you can't tell if it's a seizure or if the cat is just twitching or having like muscular contractions. Obviously, it's very difficult when animals are waking up from anesthesia to tell if you have a true like loss of conscious type of seizure. But Not sure. I've also had some cats wake up very tachycardic, heart rates like 200 to 250 and no amounts of like fluid bolusing is helping these and they just, they're just tachycardic and then it just goes away after a few hours. So after I had that experience, I just don't use it clinically anymore. I don't either. And the reason why I don't either is because the kitty that we did the D-Sulfaxone CRI,
00:53:49
Speaker
it took longer to recover from anesthesia then the duration of desthesia per se well you also mentioned that alaxone undergoes a similar metabolism to propofol so i'm assuming it's probably related kind of exactly what you talked about with propofol. And ah and I'm thinking it has to do a lot with the saturation of the metabolic processes. And that what we know, and this is another thing that we probably need to look into, is so specifically how a faxin is metabolizing the cat. Because I don't think we have that information. I am assuming that it is because of what we know.
00:54:27
Speaker
but completely determined it hasn't been done. So we've kind of unfortunately run out of time, but maybe if our audience is really interested in this conversation, we can come back another day and talk about other friend mode genes, maybe some that are related to like Molyneux hyperthermia, or just like the kind of the array of but like a clinical picture that we can see when we give opioids to some dogs. I'm thinking like giving opioids to a Husky, for example. Yeah.
00:54:55
Speaker
And so those are all really interesting, ah you know, conversations we can have maybe in the future if our audience is really interested. But I wanted to ask you a few concluding questions. And one of them is just based off of your expertise, are there any practical steps veterinarians can take today to account for Parma-Cucanic differences when they're managing anesthesia or pain in a dog or a cat?
Emerging Diagnostic Tools
00:55:24
Speaker
Okay. So basically, a couple different things that I, and this is kind of the way I approach it too, again. So, especially considerations would be, obviously, your colleagues and the use of ace-pharmacy and mbutorphanal. Okay. Yeah. What I, I definitely don't use them in that population if the MDR1 status is unknown. So that's one. So I don't use them.
00:55:49
Speaker
That's it. Simple. ah Like you said, I am cautious with the serenia if it's going to be given multiple times. And if there is any indication of the usual gallop print, I do tell them to reduce the dose in about 25%. Okay. Because we don't know. That's one. The other one is obviously our side hounds that we discussed. And be very careful with propofol. ah Be attentive to the amounts you use for induction. And I would recommend the no use in Tiva.
00:56:19
Speaker
anesthesia in these ah populations, right? And that goes also for a vaccine. Are there any emerging diagnostic tools or tests that can help veterinarians identify genetic polymorphisms related to pain management or antiseke management dogs and cats? You know, unfortunately, the only one that is widely available in the market is the MDR1 test. Yeah. that's Literally, this correlation that we're finding is the only one that's in the literature. There is one that is actually kind of gaining some traction. It's not totally related to anesthesia, but it's another genetic test that has been developed actually here in our lab, which is the post-operative bleeding test that has been developed for those eye hounds. And there is a genetic component in alpha 1-antipasmin. And there is some mutation in this.
00:57:15
Speaker
It was first reported in their hounds, but the test is now being opened to another side hounds. It's not particularly a test per se, but it's a process that is called a phenotyping cocktail. The phenotyping cocktail, in very simple terms, is basically, I give you a medication that is metabolized particularly and specifically for a route. I'm using Lextromethorphan, okay? Because it's a C2D15-exclusive substrate.
00:57:45
Speaker
And then I take some blood from you and I take some urine from you and then I go get your genotype. Okay. The test has already been standardized and has already been, it's already published. We published it at the beginning of this year. Okay. ah So it has been validated. Sorry, that's the word I was looking for. Those tests are actually done in human medicine to genotype you and phenotype you. There is a couple that have been that are in the literature in human medicine that are used for my clinicians to specifically pinpoint where you are according to certain characteristics. That's where I'm going with this phenotyping cocktail. That's where we're going. We want to use it for that purpose in particular. So basically, more to come.
00:58:27
Speaker
Great. I can't wait to get some metaphorical phenotyping cocktails with you in the future. I know. it's It's super exciting. I'm very excited about this research. Yeah. Pay attention because it's coming. Okay.
Conclusion and Invitation to Explore Further
00:58:39
Speaker
And my last question to you, if you ever want to learn about cat breeds and learn more about cat breeds, I've always wanted to go to a cat show. So would you go to a cat show? Would you go to a cat show?
00:58:51
Speaker
but but I agree 100%. All right, let's go. We should be because nobody talks ever about cat shows, but dog shows galore, right? So many dogs. Where are the cat shows? I want to go to a cat show.
00:59:07
Speaker
Me too. Let's go. Okay. Well, thank you so much for talking to me. This was a fascinating conversation. I know. Oh my God. If you want to keep talking, we can be here forever, but that's not. I know. I know. We got to wrap it up. All right. Thank you. Thank you, Bonnie. Thank you guys.
00:59:33
Speaker
Thank you for joining us today. If you enjoyed this episode, we invite you to explore the North American Veterinary Anesthesia Society and consider becoming a member. Membership with NAVAS provides incredible benefits, including access to anesthesia and pain management CE events, informative blog posts, fireside chats with board certified anesthesiologists and specialty technicians, and much more. NAVAS members also enjoy min rounds,
01:00:00
Speaker
Our long presentations on specific topics in veterinary anesthesia that offer valuable tips to use right away in practice. If you're interested, visit www.mynavas.org to elevate your anesthesia journey today.
01:00:15
Speaker
If you've been enjoying our podcast, we'd love your support. Please consider liking, subscribing, writing your review, or sharing the podcast with friends and colleagues. Every bit of listener support helps us to reach more veterinary professionals like you. For questions about this episode, or the podcast in general, or to suggest topics for future episodes, feel free to reach out to us at education at mynavas.org. We'd love to hear from all of you.
01:00:44
Speaker
Special thanks to our sponsor, Decra, for making this podcast possible. To learn more about their veterinary anesthesia products, visit www.decra-us.com. And of course, a big thank you to our esteemed guest, Dr. Tonya Perez Jimenez, for this insightful discussion on pharmacogenetics and veterinary anesthesia. This episode was produced by Maria Bridges, edited by Chris Webster of Chris Webster Productions, with technical support from Saul Jimenez.
01:01:12
Speaker
Finally, thank you to all of our gas pastors out there for spending time with us on the NavVis Podcast. Veterinary anesthesia is a lifelong journey of learning and growth, and we hope you'll join us next month as we continue to explore it together. I'm your host, Dr. Bonnie Gatson. Thank you for listening, and stay tuned next month for another episode of the NavVis Podcast.