Diabetes Drug Shows Promise Against Multiple Sclerosis
[Writer] This is research news from U-I-C – the University of Illinois at Chicago.
Today, Douglas Feinstein, research professor in Anesthesiology at the UIC College of Medicine talks about a phase one trial of a drug currently FDA-approved for use in diabetes which shows it to have some protective effects in the brains of patients with relapsing remitting multiple sclerosis.
Here’s professor Feinstein:
[Feinstein] The research that I’ve been carrying out for the past couple of years has involved designing and characterizing novel interventions for the treatment of neurological diseases, particularly with interest in Multiple Sclerosis, as well as Alzheimer’s disease.
About six years ago a post-doctoral student came to my laboratory who was interested in a class of drugs called thiazolidinedione, or more easily, TZDs . TZDs are well known nowadays because some of them are FDA-approved for treatment of type-II diabetes. There are probably about four or five million people in the United States who are taking TZDs.
There are two of them that are currently on the market for treatment. The one that we’ve used for our studies is called Actos. Its chemical name is Pioglitazone. We selected that one because it has some properties which are a little more interesting than the other drug which is on the market.
My post-doctoral student was interested in testing the possibility that Pioglitazone could have anti-inflammatory effects in cell culture models and in animals. He carried out a number of studies using primary cultures of neurons and primary cultures of astricytes showing that Pioglitazone, or Actos, reduced the production of toxic cytokines; it reduced the production of reactive oxygen species. And these are molecules which have been known to be important in the development of disease of Multiple Sclerosis.
So with that data, we went ahead and tested if Pioglitazone would have any effects in an animal model of Multiple Sclerosis, which is called EAE. And we’ve published several papers, as well as other laboratories now showing that Pioglitazone and other TZDs can completely reduce the clinical signs in the mice with an MS-type disease and, more importantly, in mice that are already ill. So we have induced the disease in the mice.
When they are treated with this drug, the clinical signs go away. So we were actually able to induce almost complete remissions in a number of mice.
This was very promising and with that type of data in hand, and the fact that the drug was already on the market and had a relatively good safety profile, we went ahead and tried to raise money from the manufacturer of the drug to carry out a small clinical trial in Multiple Sclerosis patients.
We succeeded in getting sufficient funds to do a small trial – a phase-1 pilot trial. This was done with neurologists at UIC, Rush University and with some consultation from neurologists at University of Chicago. It was done with the MRI unit at UIC, which is a 3T magnet, so we got some very good data using the imaging system here.
And what we did is we decided to recruit about 30 patients all with relapsing remitting Multiple Sclerosis over the course of about a year. And the plan was to treat them with the drug, which is a tablet, not an injectable drug. Patients like that because a lot of MS patients don’t like to get injected with interferons every day or once a week. So this is an oral drug. The clinical was to treat half of them with the drug and half of them with placebos. No one knew who was getting the drug. It was a double-blind controlled study, so the study was done quite properly.
The patients were seen initially. We ran neurological tests on them, standard for Multiple Sclerosis, and we carried out an MRI imaging to get base line values for what was going on in the brain in terms of lesions and damage to the brain. And they were treated for a year. We saw them about once every two months, and took blood samples and then we carried out neurological exams once every two months, and we did MRI scanning again after 5 months and at the end of the study at the end of one year.
So the results of the study show at the end, of the 30 patients who initially came in, only 24 really got recruited into the study. Of those, 21 completed the study. Three of them had to drop out for various reasons. There were no serious adverse effects. There were some small effects on weight gain, but very minor – but nothing to be concerned about. There were no effects on liver damage, on any blood levels, on any cytokines, everything was pretty normal in that respect
What we found is that when we looked at the neurological scores of the patients there was a slight tendency for an improvement in the group that was taking the drug. It didn’t reach statistical significance because we only had 10 or 11 patients per group. But we think that if we carry out larger studies, we may be able to detect smaller changes which are statistically significant.
The more interesting part of the study that we think is very important is that when looked at the content of gray matter in the brain – which was done by MRI imaging — we saw that the control group over the course of one year there was a significant loss in the total gray matter volume of the brain. This has been known to happen in Multiple Sclerosis patients, so we’re not the first to note that. But what was really nice to see was that in the group that was taking Pioglitazone, the loss slowed down during the course of the year. So after five months, the loss was kind of similar in the two groups — both the Pioglitazone group and the placebo group — but after one year, when the control group lost almost 4 or 5 percent of the gray matter in the whole brain, the Pioglitazone group only lost about 2 or 3 percent. That was a statistically significant difference. So what this suggests is that the treatment with the drug had some beneficial effect on the loss of gray matter in the brain. As we know, the gray matter is the part of the brain that contains more neurons.
So this was really surprising and is very encouraging. It looks like the drug may have some important effects on neuronal survival. And we’re now trying to figure out what possible mechanisms might be underlying this neuro-protective effect. We think it might have to do with the fact that, as we’ve shown previously in culture, the drug causes other cells in the brain to increase their energy supplies. So we think possibly that treatment of the patients is allowing the brain to produce more energy supplies, and increased levels of ATP use glucose more efficiently, and this is allowing the neurons to survive the toxic events that occur during Multiple Sclerosis.
[Writer] Douglas Feinstein is a research professor in Anesthesiology at the UIC College of Medicine.
For more information about this research, go to www.today.uic.edu … click on “news releases.” … and look for the release dated May 26, 2009.
This has been research news from U-I-C – the University of Illinois at Chicago.
