I'm going to give an update on the medical management of glaucoma. These are my relevant disclosures, and I've highlighted in blue the potential ones that I will be mentioning some of their products. Uh, in the in the talk, Uh, for I'm grateful that we have so many alumni that have joined us. And the virtual means by which we are presenting allows us to do that a little bit easier. So I wanted to kind of introduce you in some ways to the Gulf Home. A service. There are going to be some very familiar faces, Uh, and some new faces, uh, that you will be hearing from today. As you can see on the glaucoma service alphabetically, we are heavily weighted to the back end of the alphabet. There's at least a 15 letter separation between Dr Bernie and myself with regards to our last names. Uh, we also have our newest, um, member of the laboratory science team, doctor Shigemi Matsuyama, who's in the process of joining the department for laboratory research. So this is the outline of my talk. I want to give a brief overview of traditional medication classes made traditional meeting prior to 2018 discuss a little bit about additive therapy, uh, new mechanisms of action for the new medications and briefly touch on sustained release. So these are our traditional medications, and we've been able to magically medically manage glaucoma since the late 18 hundreds, which, for me at least, was a surprise. Um, and the advent of innovation has continued up until very recently. So with mechanisms of action are beta blockers are alpha agonists are carbonic and hydrate inhibitors are all acquis suppresses as far as outflow. And it's important to note that outflow outflow agents are preferred not just because of efficacy, but to remember Aquarius is a good thing. Uh, this is not bad. Acquis is the circulatory system for ri biotics. Rockin these inhibitors work at the tubercular mesh work. Uh, and, uh, prostaglandin analogue is primarily work through the usual scleral pathway. They do have some effect through the Trebek color mesh work, but but their predominant effect is through the Yugo scleral pathway. In terms of relative i O P lowering efficacy. This is just a quick slide comprising 150 papers or all C I s are still carbonic and hydrate inhibitors a seat is all of my dia mocks Those still remain our most powerful and efficacious medications to lower intraocular pressure prostaglandins along with the combination door Zola mine to mill all as well as. And then if you were to insert in here, but there's not a ton of evidence on it. But just their phase three studies, it would be, um, the combination between Lieutenant crossed and row Presa is also up here. Non selective beta blockers and rockin ease inhibitors would be the next most potent, uh, biotics, alpha agonists and topical C A I s would be next. In terms of efficacy, the community standard remains a first line agent to be prostaglandin analogue, we have a number of them. We have four. Tafel process is a preservative free one in terms of side effects eyelash growth, skin discoloration of the Perry overall skin iris color change to a darker, darker brown. Particularly if there's a hetero, chronic iris, uh, and peri orbital fat atrophy. So let me move on next to additive therapy, so you can consider, uh, there are four classes with which you can add to your prostate gland in beta blockers. which have the advantage of being once a day, uh, carbonic and hydrates inhibitors, which many glaucoma specialists like to use as a second line agent because of the flattening of diurnal. I hope alpha agonists have potential, Um, perhaps, uh, an advantage with low tension glaucoma over beta blockers from the lodge. It's trial, but discussing that trial it would be at least another 5 10 minutes. There's a a couple of method, a logic potential issues with the large. It's trial that it's been criticized for Rho kinase inhibitors are also an excellent added of therapy and also have the advantage of once a day dozing in terms of efficacy beta blockers and, uh, new tar saddle. The Rho kinase inhibitors are more efficacious than the other two and are both once a day dosing so with additive therapy or when you're thinking about additive therapy. Um, it's hard to ignore the question of Does it make sense to do an in class switch rather than just adding a medication? Well, um, so if you look at prostaglandin, analogue doesn't make sense, and this is probably where there's been quite a bit of literature, you know, Pro stone is only available in Japan. And so if a patient was on, you know, Pro Stone, there's at least one more paper here that shows that the Tana process is superior to Unit cross Stone for greater I o P lowering. Which is why it's not available in the United States, um, Lieutenant Cross to come across which there may be some greater i o p lowering. And here's the reference from Baniyas. Um, if you switch to travel across from Luton across, there may be some greater i o p lowering, Um, and these there hasn't really been a study that looked at going the other way. Not that it didn't show a difference. But if you switch from Burma to prostate travel process, is it possible that you might get a greater i o. P lowering with lieutenant process? It's not known. I'll give my thoughts on that in a upcoming slide. Uh, if you are a non responder, Uh, if you didn't respond, uh, then there is a possibility, and the non response rate is about 10% but it's in the studies. It's 10 to 30%. Um, in a small case series, if someone is a non responders about that 10 15% which was defined is not greater than a 20% reduction. Uh, it did make sense to switch to Luton, a process that was Gandolfi. So I do think because again, the switch papers are all looking for for switching from Luton across to something else. Um, and what is probably happening? Um, at least some component of it is that you have receptor polymorphisms, meaning that there are small genetic variability ease that aren't really mutations that cause a different confirmation or shape of the receptor and different ones. Different small molecules. In this case, prostate glands will fit into that receptor and have different levels of potency. So I think it does make sense. If you have essentially non responder to prostaglandin, whatever it is, um, whatever is your first line prostaglandin agent to go ahead and try a second one? Um, so with beta blockers, if you were starting with a selective beta blocker, then there is a decent amount of evidence that going to a non selective beta blocker is effective. There is no evidence of in terms of efficacy that's switching between the topical carbon carbon is inhibitors. There's two of them drawers. Olumide uh, and, uh, Brynn's Olumide. There's no evidence that switching between the two of them has any efficacy effect in terms of the different doses. Surprisingly, between 1.15 and two, uh, concentration. There's no change in efficacy with the selective Alpha two agonists big for monitoring. Uh, in terms of side effect profile. Does it make sense to do an in class switch? We'll hear the the even though there's no evidence or no study that has looked at switching from, uh, something other than Luton across to Luton across all the studies have shown that there is pretty much a difference with the rates of hyperthermia, Lieutenant Cross being the most well tolerated, then followed by travel across, followed by, uh, Amanda crossed. Uh, if you have a true allergy to be a K, um, Travis Tan or Tafel crossed without, uh, B A K is one option, but it is preserved with Sasha. Tafel. Process, which is commercially known as a top 10, is a true preservative free. So there are some options there. Um, if you do have, uh, some cardiac side effects, there is some potential to to go to a cardio selective beta blocker. If you really feel that, you need to stay with that class of medication. But in this day and age with so many options with other medications and we'll blazer, I'm not sure that's necessary. But there is a preservative free formulation of Tim Allal. Uh, in terms of topical carbonic hydrates inhibitors, there is, uh, some literature showing a potential difference between a stop and true stopped. It is not a mistake that I put the commercial names on here because it's the commercial formulations that were studied between, uh, in this, uh and there was theoretically an advantage with a stopped, uh, there is a preservative free version of Photoshop uh, a beta blocker combined with topical carbonic and hydrates inhibitor. And in terms of the selective alpha two agonists or Vermont sitting, there is an advantage, Uh, in terms of side effects to going with the lowest possible, uh, concentration. So when should you consider an in class switch? If there was a negligible effect, uh, less than 10% with a prostate landed. Uh, if a patient is very close to their i o P. Goal and you just want to see if you can stay with Instead of piling on another medication, you can just do a switch. It's reasonable. And certainly if there, if there's a motivation due to side effects next, like to cover our new mechanism. Our new medications. Uh, in the recent last two years, there's been lieutenant pristine Do not, Which is a nitric oxide donating prostaglandin analog and guitar saddle Aurora kinase inhibitor. Nitric oxide. Uh, synthesis generates nitric oxide, uh, in vascular endothelial cells. And in general, nitric oxide relaxes smooth muscle. So what is Lieutenant Cross Team being not? It's a single chemical compound that gets hydrolyzed in the cornea to have lieutenant crossed free acid. Uh, and then a cascade of events that result in nitric oxide. Hence the nitric oxide donation. LaTanya process works in the cell. Everybody smooth muscle cell and intra regular mesh work sells, uh, to, uh, go to the FP receptor. Both A and B. It's fairly non selective between the two sub receptor subtypes. Uh, that receptor is a G protein. A lot of mumbo jumbo happens. Essentially, you get intracellular calcium release. Uh, some magic happens. That's not been worked out well in terms of pathways. But you get a shift in matrix mental approach illnesses and the their inhibitors, their kinetic inhibitors that result in exercise and matrix remodeling and increased outflow in both celery bodies with muscle and tubercular mesh work. But again, the predominance of the effect is through the salary body, smooth muscle cells, nitric oxide. What it does is it goes into the cells of, uh, the shrooms canal and through regular mesh work what works at soluble guana light cycles. Um, some magic happens, and then you get a change. When I say magic happens, this has been well worked out, but I don't want to necessarily go into the details. But you get an act inside a skeleton relaxation, and that results in increased para celular outflow. So, Lieutenant prostate Binod essentially has lieutenant crossed when it goes inside the eye. So you can't have the same mechanisms of action that lieutenant process uses. And then the lieutenant prostate view nod, uh, component that works through the potentially the ET one receptor and may further enhance tm outflow. Clinically. Does Lieutenant Christine do not work? It certainly does. There's a series of astronomical, Uh, theme studies the Jupiter study, the lunar study, the Apollo study, the Voyager study all have shown essentially that. Not only is Lieutenant Cross team do not, uh, non inferior and better than Tim a little, uh, it is, uh, potentially, at least in one study better than lieutenant process. Rouhani's inhibitors essentially inhibit the enzyme Rockin is that they alter the and what that does is alters the sell side of skeleton and changes cellular tone, making it much more pliable and compliant. Uh, this is a slide just showing all the different pathways and by which you can inhibit rockin ease. Uh, and all these other medical, um, small molecule compounds have been tried in the past, but only, uh, new tar saddle has made it to commercialization. And again, it also not Arsenal works by, uh, enhancing para celular outfit. I just wanted to explain what that was. This is Schrems canal here, and this is gonna endothelial cells para celular. Outflow is the pathway that is in between the cells. Uh, not arsenal from laboratory standpoint causes a sort of opening or increased spaces within the tribe. Regular mesh work. It is effective in mice, which are excellent animal models effective in non human primates. Uh, and as far as patients, the Rocket one and Rocket two trials. Why everybody is why all the new medications are have an affinity towards space themed studies. Um, not Arsenal is essentially the same as time alone, so certainly not inferior. And about the same as Tim along there are a couple of unique, uh, side effects that we're not used to controversial high premiums. Certainly we're used to, but it's a little bit higher within it are settle, then perhaps some of the others and corneal deposits which it vacillates whether we call them true versus a lotta or not purchase a lotta. But either way, these corneal deposits are not visually significant. But even if they become cosmetically, uh, significant to the examining optometrist or ophthalmologist, they are reversible. So if you stop the medication, the corneal deposits do go away so briefly. I want to mention sustained release medications. Uh, the only sustained release medication that is commercially available is been mad across S. R. And it's sold under the name Doris to buy a wagon. It is an injection. So this is a picture of the injection device, and it is injected into the anterior chamber. Um, one implant contains the same amount of medication as one drop of topical Burma to process. So you're dealing with a much smaller amount of Amanda process, and the implant dissolves over about 3 to 4 months. But the intraocular pressure lowering effect can last much longer. Um, this is the size of the size of the implant, relative to the size of a of a coin of of a dime. So it's very, very small. But that's an external view. Uh, this is a Jonas Coptic view showing the implant shortly after it's been, uh, injected after it's been, uh, injected. It tends to start to swell and then slowly dissolves. This is a video of In this case, this would not be This is part of video from the study. Uh, so there's already an implant you can see here, but just let me show you what the injection looks like. This was done in the minor procedure room, and, uh, you might miss it, Uh, and then I'll just let you know. There you go. It just shot right into the inferior angle So this is a patient that already had one implant that was sort of dissolving a second implant, and then we injected a third. That was according to study protocol and not the way FDA has approved it. We'll get into that in just a moment. So this is the, uh, phase through the Artemus study. Um, and it's the phase three prospective randomized controlled trial comparing topical Batmunkha processed with, um I'm sorry, Tim. A little, uh, topical Tim. A little compared to the amount of processed implant we Although I did not make the writing team. This is team science. Uh, university hospitals was one of the sites. And you can see my name amid 50 others. Welcome to team science, but we we we have many years of experience with this implant at our center in terms of efficacy. What did the trial show? The trial show. I'm also just giving me the two minute awesome. I will not breathe for the remainder and just keep talking. But in terms of efficacy, it's not inferior to Tim Allal. Uh, and it is actually superior to Timor, as you'd expect a prostate planning to be, um, if you give three administrations what was interesting about this, and we hope that long term we might be able to get an indication. To be able to do this, you get a sustained effect for almost a year in which additional therapy is not required in terms of safety. You do get some side effects with corneal endothelial cell density loss, um, particularly with a higher dose implant, which is not commercially available, which, uh, and the incidence of this increases with multiple implants, which is probably why FDA approved this for a single injection. So in conclusion, there's a flurry of new medications and help us lower the intraocular pressure, which is a palliative measure for glaucoma. As we understand the path of physiology of glaucoma, nitric oxide, donating and rock inhibitors are certainly step in the right direction. We are getting closer and closer to to disease interrupting therapy, and we have a lot of excellent options to medically manage our patients. Thank you very much
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