What are you examining in this study?

Dr. Hess: There is only one approved drug for stroke so far called tissue plasminogen activator, or tPA is the shorthand abbreviation for it. TPA has to be given within three hours of the onset of stroke symptoms, and consequently, because of that and other fears of some of its complications, only about 2 percent of Americans that have acute stroke actually get the drug. So we are in desperate need to develop new therapies for ischemic stroke. Over a hundred different agents have been tested so far in various phases of clinical trials, and the only drug we have out of those hundred agents tested is tPA. So there have been a lot of agents that haven't made the grade. We are looking for newer agents. We are particularly excited about minocycline, because the preclinical data, the data in rodents and animals, suggests that it works up to about five hours after a stroke; and the other thing is there is some preliminary evidence that we have and others have that it may reduce the most feared complication of tPA, namely the bleeding into the brain the tPA can cause. Minocycline has been around since the 70s. It is a very, very safe drug. It has been given to millions of people. The difference here is we're giving it ultra-early to stroke patients, and we are giving it in slightly higher doses than has been given in the past.

What are you hoping this drug will do?

Dr. Hess: We are hoping this drug will be a drug that can be used literally anywhere. It will be a very easy drug to administer; it's an IV administration. It will be given rapidly in the field with few complications. So this is a drug that, eventually, we think could be used by ambulance crews, or in small hospitals, or in hospitals with very limited resources. In fact, we believe with this drug, you won't even eventually need a CAT scan before you give the drug, although in our study we are always getting a CAT scan first. The other thing we are particularly excited about -- we think this is a great drug to administer with tPA to potentially reduce the complication of tPA. So it could be a stand-alone drug, or it could be a drug you give with tPA; but it is likely to be very inexpensive because it's a generic drug, and that's been one of the problems with getting it into clinical trial -- is there is a lot of pharmaceutical companies that have shied away from stroke, and because there is not a lot of money to be made on minocycline, we have had to get NIH to fund the trial. Fortunately, the company Wyeth has donated the drug, but the only place that the intravenous form of minocycline is made currently and stored is in Japan. So we've had to get the drug from Japan, with the FDA approval through US Customs and with the great assistance of the company Wyeth.

How does minocycline work in this setting?

Dr. Hess: The minocycline is administered intravenously. That's how we are doing it in this study. In the future, there may be roles for it even given orally, but we want to get it into the patient quickly, so we give minocycline intravenously right into their vein over a period of about one hour. The nice thing about minocycline it gets into the brain very well. It has excellent penetration to what we call the blood-brain barrier. A lot of drugs haven't worked in stroke because they can't get through what we call the blood-brain barrier. The brain keeps out a lot of drugs very effectively, but minocycline gets into the brain very well. So it gets into the brain probably within minutes and gets in rapidly. It distributes in the brain, and then we think it does at least three things to make it a potentially effective stroke drug. One thing it does is it blocks this enzyme called MMP9, which is this enzyme that degrades the basement membrane around blood vessels, and tPA interestingly causes that enzyme to be increased. TPA is an effective drug. One of the things that tPA does that is probably, maybe dangerous to the brain is it increases MMP9. Minocycline blocks MMP9, at least in animal models. The second thing we think it does -- and we actually pretty much know this does from animal models -- is it blocks a lot of the inflammatory cascade. In stroke, white blood cells and resident white blood cells in the brain called microglial cells get activated, and when they get activated, they get angry, and they secrete a lot of factors which damage the brain. Minocycline is very effective at reducing the activation of these white blood cells called microglial cells and neutrophils. The third way we think it works is minocycline has what we call an anti-apoptotic function. Some cells, during ischemia, during a stroke actually die by committing suicide. We call that apoptosis. Minocycline actually blocks some of the apoptotic cascade, so we think that that's the third way it will work; and it may work by other mechanisms, but those are the three principal ways we think it will work. In a way we call it a dirty drug. It works through multiple mechanisms. It is not just targeting one stroke mechanism. A lot of drugs that have been developed and tested so far -- and all of them failed but tPA -- have been very targeted drugs that usually focus on one mechanism. The beauty of minocycline may be is that it is dirty, it works by multiple mechanisms. That may be what we need in stroke, because stroke is a complex disease where cascades are unfolding in minutes -- sometimes seconds -- and multiple cascades are unfolding the damage; and we probably have to block them in multiple pathways.

What does this drug do for the stroke patient?

Dr. Hess: We are hoping, the ultimate task for stroke drugs and what the FDA demands, and it makes good sense, is not is the stroke smaller on a brain scan, but is the patient better down the road? The typical point where we evaluate in stroke studies is three months, so we are hoping that down the road that minocycline, both with and without tPA, will make the patients more likely to be healthier and back to normal in three months. Now, we are just in the first phase. We don't have enough power in this study to answer those questions. We are trying to pick out the best dose to use in the definitive study, which we will do next. The definitive study, that study will try to address the issue, can giving minocycline early to patients who get and who don't get tPA, will it make those patients do better in three months? And it may do that by making the stroke smaller. It also may do that by reducing the risk of bleeding from tPA. In a way, we think it is a synergistic drug with tPA. It may be a nice drug to use in combination with tPA.

Will it block the immediate effects of stroke?

Dr. Hess: We are hoping that minocycline will reduce a lot of the disability from stroke. Now, stroke is the number one cause of disability amongst adults in the United States. That disability is usually motor; there's a paralysis. That's a big cause, and that's certainly a major cause of disability from stroke; but stroke also causes aphasia and difficulty to speak. It also causes cognitive problems, and we probably only see the tip of the iceberg. There are a lot of strokes that are silent that probably lead to dementia; that are minor strokes in themselves but lead to major problems. Now, it's going to take a long time to unravel this. In most of our preclinical development with minocycline, of course we test it on rodents, and it certainly improves their motor disability. So we are hoping that minocycline, to use the analogy that is sometimes used, will get the patient who, instead of being in the bed, bedbound, for the rest of their lives, may be able to use a walker; or the patient who is using a walker to maybe get to the cane level, and the patient who is using a cane to be independent. We can't expect it to be a Lazarus effect, so to speak, where it's going to take every patient we give it to and get them back to normal. That would be unrealistic, but a small increment of change, a reduction of some disability, would have a major impact in a disease right now where we have only one drug treatment that works.

How did you translate an antibiotic into a potential stroke treatment?

Dr. Hess: This is why the NIH funds basic research. This was kind of, in a way, an accident. Some scientists out in California at the time had made the observation that this drug works very well at reducing inflammation. That was well-known. It is an anti-inflammatory drug. Since stroke has an inflammatory component -- that is, inflammation and white blood cells being angry makes stroke worse -- they reasoned, well, let's try it and see if by reducing inflammation we can make the stroke smaller in rodents. That experiment worked. It was published in 1999. We and other labs started working with it after that and started changing the formulation around. Initially, it was given in very high doses intraperitoneally -- we call it intraperitoneal injection. We starting changing that and trying intravenous doses, and we found, lo and behold, that an intravenous dose that was safe in humans also made the stroke smaller in these rodents. Then we and a lot of other people working with minocycline have found other ways we think it would work. So minocycline has been shown to reduce stroke by multiple labs and in multiple animal models, and to work by, probably, multiple mechanisms. Again, it was one of these, like scientists often do, they tinker around with things. This was not a drug that was developed by the drug company for stroke, per se. It was developed by the drug companies for infection. They have actually come out, the drug companies, with better minocyclines for infection, but the one thing that minocycline does better than all the other tetracyclines is that it gets into the brain really well. That's why we like it. It has the best penetration into the brain of the entire tetracycline family. So the drugs like tetracycline, they don't get into the brain well. There is a drug, doxycycline, that gets in the brain a little bit, and that probably works for stroke; but minocycline gets into the brain the very best, and by our reasoning, it's probably the best drug to use for stroke.

Tell me about Jerry.

Dr. Hess: Jerry is a about a 49-year-old gentleman who had some risk factors for stroke and had a history of a carotid occlusion, but was doing well. He was at work, as I recall, at the jail when he suddenly couldn't speak, couldn't get his words out. While he was being watched, the right side of his face drooped down, and he had trouble using his right arm and a little bit his right leg apparently. His co-workers did a great job, because they called 911 and they brought him to Jefferson County Hospital, which is a small rural hospital, who, when they saw him immediately, made the decision to call us and enact the Telestroke Reach Protocol, where a neurologist here provides telestroke consultations with Jefferson County doctors. He was evaluated by that system, found to be having an acute stroke, and they got him there really quick. He was treated in under two hours with tPA. So he was given tPA or tissue plasminogen activator at Jefferson County Hospital, which is a small, certainly under 75-bed hospital approximately an hour from us. One of our physicians who did the consult knew about our trials, so we brought him up here. Anybody who gets tPA at one of these rural hospitals generally comes here so any complications can be managed, so we got him here. When he got here, we were waiting for him, and he was already improving somewhat. He improved in the ambulance up here partially from the tPA. So his stroke was partially better from the tPA, but he still had trouble talking; and his speech was very, very slurred, not like it is today when you interview him. He also had severe right facial weakness. We talked to him and his wife, saying, you've got the only drug that works, and we told about the minocycline trial. Now, this was all done with a long, informed consent that we have to explain to him and his wife. So we explain it to them we have this drug, it was being tested, and both he and his wife conferred about it and made the decision to go into the trial. So right there in the ER, we went up to the pharmacy. We brought the drug down. It is unmistakable -- the drug discolors the fluid; it all looks yellow. So we ran this yellow bag of fluid into him and we got him treated; we started the minocycline treatment in just under five hours. If you think about, the guy started in Jefferson County in the jail at work, had a stroke, got tPA, got partially better but did not get totally better; and you never know if someone is going to continue to get better when they start getting better, or whether they -- sometimes they worsen again. So we put him on minocycline and then we admitted him to the hospital. This was over Memorial Day Weekend. I remember it well. We put him on our Patient and Family-Centered Care Unit in the Health System and promised him a window, a private room. He got it, we called it the suite, the executive suite. He stayed there, and we continued the drug for three days. It was the Memorial Day Weekend. In the study, you get the drug IV as soon as you hit the door, and then you get five more intravenous doses; and while he was here, then we collected some additional blood from him to see if the minocycline reduces these collagenases in the blood. I mentioned MMP9, and then we did some pharmacokinetic studies, which we don't have analyzed yet. This just happened. So he gradually got better. By the time he left, his NI stroke scale score, which is a measurement of stroke from zero being where you are now -- I think I may be a one or two -- and 42 points being the worst. He started at Jefferson County being about a 10, as I remember; and when we enrolled the study, I think he was a five. By the time he left the hospital, he was one point; and when I talked to him on the phone in the last, I thought it was his son talking, because his speech -- which was slurred -- was the one thing that hadn't totally recovered. I mean, I thought I was just talking to a regular person. I haven't seen him back. We are going to see him back soon again. It sounds like he returned virtually to normal. So here is a young man, 49 years old. What helped him? Well, the tPA certainly helped him. Did the minocycline help him? Well, I don't know. That's the drug under investigation. We found that in him, the minocycline was safe. It did not cause any concerns; nausea, vomiting. Of the concerns about getting minocycline is it causes some sclerosis of the veins. We did not see any of that. So in him it was very safe. It has been very safe in our first two patients; but you know we have to continue on, because after we fill dosage, then we are going to go with higher doses.

What is your gut telling you about the eventual results of the study?

Dr. Hess: I'd like to believe it is something that we did; but it's really too early to tell, because there is some spontaneous improvement in stroke patients, so I don't want to make too much of an anecdote. I'm certainly convinced that the tPA led to a large improvement in him; but did the minocycline additionally help and prevent it from bleeding from tPA? I don't know. Of course, we are excited to do this, and it's a passion we have; but as a clinical investigator, you also have to step back sometimes and not be too carried away until you do the definitive double-blind trial. In this trial, everybody gets the drug, and we are not blinded. The definitive study is when you are not biased and not blinded. So I'm sure, like all investigators doing a study, we have some bias whether we like to admit it or not. I'm sure I have a lot of bias here, but I like to believe in the first two patients that we did something to help them. Was it the tPA, was it the minocycline, was it the combination? You know, only time will tell. Hopefully, if you come back in five years or six years, we'll have the results of the definitive trial, and then we'll know whether minocycline works; but if it works, the beauty of minocycline will be it will be a drug you can use literally anywhere, and it should be relatively inexpensive to give.

It's exciting when you have very little that works in patients and you see patients all day long who, for a variety of reasons, don't get any treatment because they get to the hospital too late, which is usually the case. Yes, it's exciting because we don't have a lot to offer. There is still a lot you can do for stroke patients in terms of rehab. Don't get me wrong, but you'd like to intervene in the first few hours.

So this is a possibility for the future?

Dr. Hess: I hope so.

END OF INTERVIEW

If you would like more information, please contact:

David Hess, MD
Medical College of Georgia
Augusta, GA
(706) 721-1691
http://www.mcg.edu

This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.