Thank you, Thomas, and good morning, everyone. And thank you for our speakers for going over the basic immunology of sepsis and COVID. That was very helpful. So, I'm going to be ending it with talking about a whistle-stop tour of drugs, just some of the most recent immunology – some drugs related to immunology that some – some critical care specialists can see in the ICU. And this was pretty helpful. It reminded me, actually, of my PhD days where we were looking at myoid-derived suppressor cells related to sepsis immunosuppression. But I actually also recently completed my fellowship with the SIP Center at Vanderbilt University Medical Center. I have no conflicts of interest to disclose. And pretty much, I was invited to talk about some of the rare drugs that clinicians can see related to the fields of diabetes, rheumatology, and endocrinology. So, pretty much, I'm going to go over when it was approved, what its main uses are, the main mechanism of actions, some of the dosing parameters for that, some of the main side effects, and finally, some of the main monitoring parameters. So, the first drug I'm going to be talking about is related to diabetes. So, it's terdzipetide. And this is pretty much a weekly subcutaneous injection that's given to patients. It was approved around six, seven months ago here in the U.S. and then shortly after it was approved in the UAE, followed by Europe, and most recently, last month, it was approved in Australia. So, like I said, it is used for type 2 diabetes patients. And pretty much, what happens is that in these patients, the encrintin effect is usually dysregulated. And the encrintin is pretty much what causes that insulinotropic effect, which increases insulin sensitivity and is also stimulated by nutrients or by food. And so, what happens with this medication, how it works, is that there are two hormones, GLP-1 and GIP, that are also involved in this encrintin response. And so, this medication is pretty much a double receptor agonist of both GIP and GLP-1. And so, pretty much, after patients consume food or after the consumption of nutrients, this medication binds to both receptors, both GIP and GLP-1, causes that increase in encrintin effect, which increases insulin sensitivity, decreases blood glucose, as well as delays gastric emptying. And this last effect of delaying gastric emptying is pretty much related more to the GLP-1 effect more than it is for GIP. And now, some additional studies have shown that GIP can actually increase glucagon. And this is pretty much not really, you know, not what we really need in this situation. However, it was shown that it increases glucagon more in hypoglycemic patients, more, and it actually does not have any effect in patients that are either hypoglycemic or have normal glucose levels. So, for the dosing, like I said, it's pretty much a weekly injection, similar to some other GLP-1 agonist medications that starts as a dose of 2.5 milligram. And after four weeks, an increase in dose can happen if needed, as well as to a maximum of 15 milligram once weekly. Of course, it is important to monitor the glucose to see if the medication is working and what's happening to this patient with their glucose levels. There might be some GI changes that can happen, and it can be severe if the patient is dehydrated, as well as, you know, some pre-renal AKI can occur if they're – especially with dose increases and long periods of using this medication. So, the second medication that I'm going to be talking about is Mitopivate. So, this is pretty much an oral tablet that was approved around 11 months ago. And this was – this is actually the first FDA-approved drug for patients – for adult patients with hemolytic anemia that are related to having a pyruvate kinase deficiency that pretty much affects the RBC glycolysis pathway. And so, in these patients that have a pyruvate kinase deficiency, these patients sometimes have a – have a deficiency in this RBC form of their pyruvate kinase, which pretty much leads to that decrease in ATP, decrease in RBC lifespan. However, how Mitopivate really comes into action over here is that it binds on an allosteric site to this RBC form of the pyruvate kinase, which then leads to an increase in pyruvate kinase activity, which increases the affinity of the pyruvate kinase to its substrate, phosphoenolpyruvate, increasing pyruvate, and also affecting the overall – affecting the RBC glycolysis, which increases ATP and RBC lifespan. Now, for these oral tablets that's given for – for this indication, it's pretty much given twice daily for four weeks, and then an increase in dose can happen to a maximum of 50 milligrams twice daily. Now, what's important about this medication is that it's – you don't really have – you don't – you are not supposed to stop it all of a sudden, because this can increase the risk of acute hemolysis. So, just, you know, slowly tapering down the dose before discontinuing it might be the best option. Now, looking at hemoglobin levels, if they are low, or if the patient needed a transfusion recently, then this might indicate that we need to increase the dose for this patient, as well as vice versa with the hemoglobin levels if they – if there is an increase. We need to look at gout patients, because there is a risk of increasing uric acid levels, as well as it can cause a decrease in estrone and estradiol levels due to it being – acting as an aromatase inhibitor. And the last medication that I'm going to be talking about now is called efgarticamode, and this is pretty much a IV injection that's given for patients with myasthenia gravis, and usually these are going to be given at, you know, infusion sites or infusion clinics for these patients. However, some of the patients that end up coming to the ICU might also be on it. So, pretty much just as a refresher, myasthenia gravis is a chronic autoimmune disorder that causes a weakness in patients in their voluntary muscles due to a disruption in the nicotine acetylcholine receptor activation. And so, especially in – and this is especially in patients that have a antibodies positive for acetylcholine receptor. Now, how this – pretty much how this medication works is that there is a receptor called neonatal FC receptor, and this receptor, once it binds to its ligand and it's activated, it pretty much is responsible for recycling IgG levels in the – circulating in the system in the patient's body. And so, from these IgG levels that circulate in patients that have myasthenia gravis, this also circulates and increases the number of antibodies against the acetylcholine receptor. And so, this increases or aggravates the symptoms of myasthenia gravis. So, how this medication pretty much works is that it's made up of a human IgG antibody fragment that, once it binds to this receptor, it actually blocks the activity of this receptor. And so, it decreases the recycling of the IgG1 in the patient's body. And so, it decreases also the harmful acetylcholine receptor antibodies, which hopefully would decrease the symptoms of myasthenia gravis. The dose is pretty much, like I said, it's given as an IV injection. It's also given once weekly, and it's only for four weeks. Because this medication has a risk of, you know, decreasing the IgG levels, which are important for our immune system, there is an increased, you know, an increased risk of infections. So, it is important to, you know, of course, monitor the white blood cells, monitor the neutrophil count in these patients, because they can especially have an increased risk of urinary and respiratory infections. Like any IV injection that's being used, especially if it's going to be affecting the immune system, of course, and like most of the medications, there can also always be an increased risk of allergy from patients. So, also monitoring any hypersensitivity reactions from these patients is important. And with that, I conclude my whistle-stop tour. I know it was pretty quick, but I will be happy to take any questions if anyone has any. Thank you.

diabetes

hemolytic anemia

myasthenia gravis

terdzipetide

Mitopivate