Thank you for allowing me to present here. This was partially funded by federal funding. And I want to start by just explaining why are we even using intrathecal nicotinophen. So subarachnoid hemorrhage is an uncommon type of stroke, but it does carry a disproportionate high long-term illness burden. And about 40% of survivors cannot return to work. One of the complications that patients do suffer is delayed cerebral ischemia, which is a main driver of their long-term functional outcome. So delayed cerebral ischemia, by definition, is delayed, which means that we potentially have room to intervene. And that is the focus of this intervention specifically. There is an association between vasospasm, that is very common, and then later development of delayed cerebral ischemia. And we have been using, for quite some years, nicotinophen, a known contenture blocker, as means to alleviate vasospasm. Now, delivering nicotinophen intrathecally has the opportunity to deliver the drug in a relatively smaller dose, right where it's needed, right where the blood vessels travel. Now, we published our experience previously, and we were able to overall describe 422 patients who received intrathecal nicotinophen. We gave doses that range between 2 and 5 milligrams every 4 to 12 hours. Usually started around day five, which is the peak day for vasospasm detection. And patients were usually treated for about seven days. Now, because we gave the drug to almost everyone that needed it, we did not have a control group, so we did compare it to an external cohort called the SAHIT cohort. And our results demonstrated that delivering intrathecal nicotinophen was associated with lower rates of delayed cerebral ischemia and higher rates of favorable outcome at three months, defined as modified drinking at two or below. So our interim conclusions were that intrathecal nicotinophen is a feasible treatment, and it is associated with better outcomes. But we had two major questions that we had to answer right away. One is, what is the actual mechanism of treatment? That is not completely clear. And then also, what is the optimal dosing? Because our dosing regimen is very variable. So as for mechanism, I invite you to join us tomorrow where we're going to present some data about potential mechanisms. And as for this presentation, from the larger pool of patients that were monitored in order to identify the mechanism of action, we did do a smaller study looking at the pharmacokinetics of intrathecal nicotinophen. Now, this is potentially an interesting question because it's not very common to deliver intermittent dosing intrathecally. Most intrathecal interventions are one time or one every few months, or maybe with a reservoir with continuous delivery. But intermittent delivery is not common. It's also interesting because we're delivering it into the ventricular system when it has obstructive hydrocephalus. So this is not a normal system, and even trying to assess volume of distribution is very difficult. So what we've done is we really did an observational study. These are patients that received intrathecal nicotinophen as part of usual care. This was approved by our local IRB, and we got informed consent from everyone. This is preliminary results on 12 patients that were treated, and we had samples collected and analyzed. In addition to the fungal kinetic element, we also looked at frequent vitals, ICPs, and adverse events that I'll show you in a minute. We did collect hourly CSF, and this is important to stress that this is not CSF that we drew directly from the EVD, from the drain. This was CSF that was spontaneously drained, and we just collected that on an hourly basis. We also did some plasma sampling. In addition, we measured not only nicotinophen but also namodipine. As some of you probably know, all of subarachnoid hemorrhage patients per protocol per standard of care are supposed to be on a namodipine regimen, and we measured namodipine just to make sure that we are measuring specifically nicotinophen and namodipine, and the analysis does not combine the two. Study population was pretty straightforward, kind of classic presentation of subarachnoid hemorrhage. Patients were in their mid-40s. Most of them were women. In terms of severity, it was a diverse group. WFNS was a median of two but ranges all the way from one to five, which is the entire range of WFNS. The modified Fisher grade, which is a grading system to say how much blood is on the initial CT, was four, which is the maximum, and in terms of number of nicotinophen doses that these patients received was variable, 34 plus minus 22. First, in terms of the safety parameters, this is, as I mentioned initially, there was a bigger cohort, and from that we did a smaller cohort looking at PK, so from the bigger cohort, we looked at ICP and blood pressure, heart rate, and we really saw that there was no statistically significant difference when we delivered intrathecal nicotinophen. There was a very slight increase in ICP initially, but that is really due to the fact that when we inject intrathecal nicotinophen through the drain, we clamp it for about 30 minutes, and so that slight increase is really during those 30 minutes, and after we open the drain, then that goes straight back to baseline, so no signs of harm and no signs of systemic absorption and effect, at least on average, but when you look more specifically, we looked at adverse events, 25 patients in this specific analysis, and we saw that transient ICP increase above 25 were the most common adverse event, happened in 11 out of 25 patients in 35 separate doses, and mostly that happened during the first few doses and did not continue to happen throughout treatment. Headache was the second most common, kind of what you would expect, in about 20%, and again, mostly during the first dose. Also, we noticed nausea, vomiting, symptomatic hypotension happened in a single patient in a single dose. Ventriculitis, this is something that we all fear when we deliver something intrathecally, that happened in two patients, but in both of them, the diagnosis, the symptoms and diagnosis of ventriculitis happened way over a week after we finished treatment, so we don't think that this is related to treatment. One thing to watch that we need to further look into is the rate of VP shunt, or the need for kind of chronic CSF diversion. That was extremely common. It is also very common in this patient population, but it's unclear if nicotinamide had any role in that. We had one patient that refused treatment after the first dose because the headache was unbearable. And now, as for the pharmacokinetic results, again, we measured hourly CSF during the first dose, and then we chose another delayed dose day three. We did not know when steady state would be achieved, and so we kind of assumed a priori that by day three we should be there, and that is the reason for that day. And you can see kind of the expected general increase in concentration than a general decrease on this is day one. You can also notice the almost negligible systemic absorption. Really, the plasma concentration is very close to zero, especially when compared to the CSF-1. And then the lower graph looks into the delayed day three dose. What you can see is that we're definitely at steady state because the concentration at time zero is very close to the concentration at the end of the dosing regimen. And we did have some patients who had Q6 dosing and some who had Q8 dosing, and there was not a drastic difference between the two. Again, the systemic absorption on day three was also negligible. As I mentioned, nimodipine was co-measured. The results were nearly zero in the CSF, which is also an interesting finding. And then the results are obviously limited. It's only 12 patients, and the variability is extremely, extremely high. We do have more patients that we collected, and we're waiting for their results, so stay tuned for that. These results helped us a bit but also left us puzzled, and there are definitely some serious limitations. One thing to mention is that we delivered a drug in the dose of milligrams, and we got back a concentration in nanograms, and that kind of posed the question, where did it all go? And with the half-life that we calculated, roughly around two hours, which is similar to the systemic half-life that we know of, it kind of puzzled us. So we're looking at different options. One option is that, again, we're collecting from the EVD collection system, and we are not taking it directly from the patient to reduce any risk for the patient. So it might be that some of it gets absorbed into the plastic, into the tubing. Another option is that there is a short-term systemic absorption that we're missing because we sampled plasma after an hour, and maybe there is some absorption in the first few minutes. And another option is that it could be that it's being metabolized very fast in the brain. We know that there are certain SIPs that are able to metabolize nicotine, and they are active in the brain. So we do need to perform more studies to validate these results, both by increasing the N, but also trying to find alternative explanations as to why the concentration is so low. When we have more data, we're hopeful that we could also perform a pharmacodynamic study and really try to assess the correlation between nicotinine concentration and the effect. And most importantly, we feel that it's been enough time that we've been using interstitial nicotinine as an off-label intervention, and it is time for a clinical trial to really know if this treatment is appropriate and needs to be done really worldwide and not just in a few shops. So with that, I will conclude. I do want to especially thank not just my co-authors, that some are here, but also I want to thank many nurses, APPs, current and past fellows, who diligently collected those samples across many, many hours, across many, many patients. So without them, that would not be done. So thank you.

intrathecal nicardipine

delayed cerebral ischemia

subarachnoid hemorrhage

pharmacokinetics

clinical trial