Interstitial Cystitis Network - Meet the IC Expert Guest Lecture Transcript
Date: February 19, 2002 
Topic: Mast Cells, Hydroxyzine, Algonot and IC
Speaker: Theoharis Theoharides, MD. Professor of Pharmacology & Internal Medicine, Tufts University, Boston MA.
Moderator: Jill Osborne, ICN Founder

We would like to thank our sponsors, Algonot, AKPharma (makers of Prelief), and Farr Laboratories (makers of CystaQ) for underwriting this special event. The ICN Meet the IC Expert Guest Lecture Series currently serves patients and providers throughout the world who are searching for the most up to date information on IC patient care, new research studies and treatment strategies. Our lectures are free to all and usually occur several times a year via the ICN web site. To receive announcements for upcoming events, please sign up for the ICN e-newsletter at: http://www.ic-network.com/newsletters/  

(Jill Osborne) Tonight we welcome one of the great IC researchers who has made time in his busy schedule to come visit the ICN, discuss his latest research and to take questions from IC patients. Dr. Theoharis Theoharides is originally from Greece. He came to the US in1968 to Yale University where he worked until 1983 when he moved to Tufts University. Dr. Theoharides is currently a Professor of Pharmacology and Internal Medicine at Tufts and is constantly visible in IC circles for the research that he has done with mast cells, hydroxyzine, and his participation in the NIDDK IC Clinical Trials Group. Dr. Theohardies currently serves on the scientific advisory board of Algonot LLC and will talk tonight on his most recent research with quercetin, glucosamine and chondroitin.

(Jill Osborne) Dr. Theo, Welcome to the ICN! How did you first get involved with IC?

(Dr. Theoharides) Thank you very much. Almost 15 years ago, Dr. Grannum Sant (who is now chairman of urology at Tufts New England Medical Center) asked me to discuss a patient with him because some of the symptoms were somewhat reminiscent of allergies. After conducting a biopsy, we were amazed to find out that the bladder tissue had a lot of mast cells and that they were activated. Activated means that they were secreting molecules and that they were not normal. The amazing thing was that this was a man. We published the first report of IC and mast cells in a male patient ever, about 12 years ago, and since that time, we have been working with Dr. Sant closely.

In the course of these studies, in addition to mast cell research, we were among the first to notice, as physicians, that many patients also had other conditions, such as allergies, IBS, migraines, and fibromyalgia. Since then, at least two additional reports have actually proven that these other conditions are unusually high in IC patients. Because many of these conditions also have mast cell involvement, we started thinking that maybe IC was a bladder reflection of a more general problem and that the underlying mechanism may be the same in the other tissues involved in the other conditions. That was fascinating not only because it may explain these other conditions but because it allows us to use the findings from the bladder to understand the other conditions where biopsies are much more difficult to obtain.

I have remained active in IC research even during periods when we had absolutely no funding. Most recently, we have added what I consider an important correlation. About four years ago, we had evidence that in animals acute stress could stimulate the bladder mast cells and promote inflammation in the bladder. Over the last year, there have been two publications from another medical research group showing that acute stress does worsen IC symptoms in most of the women that were studied.

Right now, we not only have an animal model we can study, but also a series of compounds that may prove to at least inhibit the worsening of the symptoms by stress and that such compounds could be added to others in use for IC. The current and possible new drugs for IC were reviewed recently by Dr. Sant and me in a new article. That publication will be posted on the ICN shortly. (http://www.ic-network.com/library/IcDrugs2001.pdf)

(Jill Osborne) You've brought up a tender subject. Some patients may interpret that to mean that they are causing their stress?? Is that what you mean??

(Dr. Theoharides) No, we don't mean at all that patients are causing their problems. Over the last 2-3 years, there has been a lot of new information that shows that when humans are stressed (either physical or emotional stress), a hormone that we thought is released only in the brain is also released outside the brain in various organs. When it is released in those organs, such as the bladder, it promotes inflammation. So, it has nothing to do with what we wish or not wish. It is totally unconscious.  Now that we know which hormone is being released, we have a target to possibly block and hopefully reduce those symptoms.

(Jill Osborne) It's very normal for patients to flare if they are exposed to cold... because of that physical stress.. right?

(Dr. Theoharides) Yes.. that is correct. There have been publications on atopic dermatitis, also known as cold-induced itching, which is well known to be worsened by exposure to cold. So it's not only the bladder that might be involved. Two other examples, migraines and IBS, are also very well known to worsen by stress, such as the physical stress of staying up at night to write a paper. Now, for the first time, physicians are starting change their minds and believe that stress is a real issue rather than what you said earlier. People don’t bring it on themselves. In fact, an article and guest editorial of mine will appear in April in the Journal of Clinical Psychopharmacology which is called "Mast Cells and Stress." For the first time ever, it is pulling facts together with hard evidence to support the real association between stress and inflammation.

(Jill Osborne) Would you describe, briefly, mast cells and what they do?

(Dr. Theoharides) Mast cells technically belong to the immune system and they come from bone marrow. But, until about five years or so ago, we only thought that they were important for allergic reactions. I sometimes describe the cells to students as soccer balls filled with about 500 ping pong balls. Each ping pong ball contains about 30 important molecules and when these cells are stimulated (i.e. by an allergic reaction, for example) all of those molecules come out along with about ten more which are not inside the ping pong balls. These last ten are known as secretory granules and are made during the reaction.

All of these can cause detrimental effects, such as itching, difficulty breathing, pain, diarrhea, when they are released. In the bladder, they cause pain and inflammation, as well as frequency and urgency because some of the molecules released stimulate the local nerve endings which make you go to the bathroom. In addition, some molecules released act like meat tenderizers and destroy the lining of the bladder and, therefore, create additional problems since the bladder is not protected anymore.

This doesn't mean to say that the mast cell is the beginning and the end of IC but once they get stimulated, they continue to promote all of the problems regardless of what might have been originally the cause.  So we took the approach that the best way to reduce IC symptoms, if not hopefully treat, would be to combine some drug that can inhibit mast cells along with something that might help the bladder create new lining.

Seven years ago, our first approach was to use hydroxyzine (aka Atarax or Vistaril) because of the ability of this drug to do four different things.

1. It inhibits mast cells somewhat.. but not 100%
2. It inhibits the activation of local nerves, somewhat.. also not 100%
3. It blocks the neurotransmitter acetydcholine which makes the bladder go –  Hydroxyzine is anti-cholinergic like other drugs we use to reduce frequency.
4. It can reduce anxiety.
5. It is sedating so that people who get up at night often can be helped.

Now that doesn't mean that all of the patients will respond to this drug but it was so cheap and we felt we had nothing to lose by starting to use it. 

One of the problems from the beginning was (and is) that when physicians hear hydroxyzine, they prescribe patients with a high dose of 100 mgs a day. That dosage would put an elephant to sleep. Instead, what one should do is start a patient at 25 mg at night for a week and usually that sedation goes away within one to two weeks. Then advance the dosage to 50mgs at night and wait 1-2 weeks. That’s a critical point because if the patient still feels sedated after that they should stay at 50. If they aren't very sedated, then they can go to 75mgs. Usually it is 50mgs at night and 25mgs sometime before noon.

The second critical part is that you must stay on the drug for at least 3 months. Many physicians and/or patients don't know this and when they experience a slight sedation, they stop taking it.   All they have to do is stick with it at the dose that they can tolerate for a few months. I would say that most of the patients, by six months, will get some relief though it may vary to what extent or symptoms

When the IC trials group was formed by the NIH, they asked for applications from which they would choose the first drug to use in this clinical trial. Our application to compare hydroxyzine to Elmiron was selected. This trial is currently ongoing and all the patients we were aiming to enroll have been enrolled. We should know the results about a year from now. These trials will tell us whether hydroxyzine by itself is effective and whether added to Elmiron, might give us better results. In other words, hydroxyzine compared to Elmiron, and the combination of the two as compared to a sugar pill (placebo).

(Jill Osborne) You also discovered that Elmiron appears to effect the mast cells in the bladder.. right?

(Dr. Theoharides) Correct. Elmiron is like a molecule that is found inside the mast cell granules. We thought that it might act on the mast cell to block it and the reason we thought  that is because the molecule inside the granules is chondroitin.  In fact, 50% of the content inside each granule of the mast cell is chondroitin. So we decided to see if chondroitin could block the mast cells and whether Elmiron would also do the same. And we actually found and published the results that show both are very strong inhibitors of mast cells.

In addition, you may know that the lining of the bladder is made up of two molecules: chondroitin and hyaluronate. We decided to see if hyaluronate would also do the same and in the January issue of Journal of Urology there is an article which shows that hyaluronate also blocks bladder mast cells and inflammation. So now we had choices of molecules that would not only block mast cells and inflammation, but also help cover the lining of the bladder, which, in many patients, is at least partially destroyed.

If I had my choice, I would try to combine hydroxyzine with one of these molecules that would cover the GAG layer. The first part of combining hydroxyzine and Elmiron will be dealt with in the clinical trial we discussed earlier. We will also try to see if there are any natural molecules, not drugs, that might allow us to do what hydroxyzine and Elmiron might do.

Chondroitin and quercetin are ready made, natural and not drugs. Chondroitin blocks the mast cells and helps the new lining. Quercetin is very important in blocking inflammation. The question is, can we give something to the body to make new lining from scratch? The building block for the part of the lining is glucosamine so we then said let's use the glucosamine, and chondroitin and quercetin.

That sounded wonderful but there was a major problem. Chondroitin is a large molecule and can't be absorbed well.  Less than 5% of any GAG can be absorbed by mouth, which is why hyaluronate is being given intravesically. Bioniche is now marketing chondroitin intravesically as of a few months ago. So we really wanted to give it by mouth, which meant that we had to find a way to increase the absorption.

The same is true for quercetin.  It's not a large molecule that likes lipids and not water. In other words, it doesn't go into solution with  water but it does go into solution in oils. Less than about 10% of quercetin as powder is absorbed so we decided to use what our body knows how to do very well. Our intestines are extremely well suited to absorb oils. We chose to mix glucosamine, chondroitin and quercetin in various oils and tested to see which one would give us greater absorption. We tried codfish oil, primrose oil and it turned out that olive seed oil is the best.

What’s olive seed oil? Once you get the olive oil, you're left with the skin and the bits which, when that is crushed, creates olive seed oil which is 10 times richer with antioxidants.

So, since you can’t use an oil in a pill or a capsule, we found a company that made soft gel capsules which included these ingredients and the oil. This is what we call Algonot Plus.

(Jill Osborne) You’ve expressed concern about the quality of these ingredients provided by other companies. What is your concern?

(Dr. Theoharides) One of the things that we should watch of anyone who sells chondroitin or quercetin is when they do not state what the source of the material is. This is important for two reasons. One is that most of the sources of chondroitin in the USA are actually from cow trachea imported from Europe and that runs the risk of catching mad cow disease. These products are banned in Europe but are still imported here in the USA because they are not considered "drugs." In Algonot, chondroitin is from shark cartilage, which avoids this problem.

Secondly, quercetin, most often, comes from fava beans but about 50% of Mediterranean people lack an enzyme. If they eat fava beans they can develop anemia. In Algonot, our quercetin comes from a plant called sapphora to avoid that problem.

(Jill Osborne) Don asks the first question. Would this treatment help with Hunner's Ulcer?

(Dr. Theoharides) Once you have an ulcer that means that whatever you choose to use will definitely take longer to respond. Very few treatments so far have been very successful once you have Hunner's Ulcers but, I believe that given time, this is likely to help but I cannot predict how much. Let me clarify. Medical treatments might not be helpful but surgical or laser treatments have been used effectively and successfully for Hunner’s ulcers. No one has tried Algonot before but I expect that some help should be experienced.

(Jill Osborne) What kind of results have you seen with Algonot... and I'd like to know how the company got started?

(Dr. Theoharides) The company got started by two patients of mine with lots of allergies (but not IC) who were so impressed by the relationship between stress and mast cells that I've described tonight, they decided to form a company to bring this product to the patients. If any money would be made, it will be turned into research for IC and related problems.

The first research was in animals and it was very encouraging. So far, the feedback that we have from the patients that have been on it for three months or more has been very positive, including some patients that have reported that for the first time ever their fibromyalgia got better. A small trial is also being planned to be conducted at the New England Medical Center.

(Jill Osborne) Peiti asks if olive seed oil is acidic.. and will that bother an IC patient. Great question Peiti!

(Dr. Theoharides) The oil has as low an acidity as olive oil and it's not going to bother the bladder. I always tell patients, however, that anytime you use something for the first time you always have to be cautious. If one were to go buy olive seed oil anywhere, it could be acidic because they usually let it sit for months. Our oil is imported directly from Crete, which provides the olive seed oil within a week of its collection. If olive oil stands around, it gets oxidized and then it becomes acidic.

(Jill Osborne) Lisa asks if any other medication besides hydroxyzine.. (i.e. an antihistamine) can be effective at reducing allergy symptoms and, of course, IC?

(Dr. Theoharides) I'm surprised that hydroxyzine didn't help your allergies at all. No other antihistamine has been shown to reduce IC symptoms so far. Some tricyclics that also have an antihistamine as effective are Elavil and Sinoquan. None of the over the drug allergy drugs will be helpful.. for the reasons we described earlier.

(Jill Osborne) Susan asks “Will Algonot interfere with Elmiron?”

(Dr. Theoharides) It should not but because they are similar I would keep the Algonot at no more than 3 capsules at day rather than the six capsules maximum that people can take. That's only my gut feeling because we found that they acted similarly. I don't have evidence to back that up. There is no problem with hydroxyzine, tricyclics or pain meds with Algonot but I would suggest that they take Algonot with food and not on an empty stomach because of the olive seed oil content.

(Jill Osborne) Any comments on DMSO???

(Dr. Theoharides) My colleagues only use DMSO on more severe patients these days. They'll usually start with the hydroxyzine. But if someone has more severe ulcers, I would prefer that they start with the DMSO and then go on to the other treatments rather than starting with the oral medications first.

(Jill Osborne) What’s your thought on what DMSO does??

(Dr. Theoharides) One of the prevailing views is that DMSO depletes both nerve endings and inflammatory cells of their noxious molecules which is why it causes pain in many people upon instillation.  Then the body takes some time to replenish that stock. During that time patients get relief.

(Jill Osborne) Do you believe in hydrodistention for diagnosis?

(Dr. Theoharides) Yes, because in patients that have very mild symptoms and we’ re not sure what the problem is, hydrodistention will add information that will make the diagnosis possible. In patients with classic symptoms, you probably don't need that. In addition, hydrodistention and a biopsy may permit the exclusion of other more serious diseases that sometimes confuse the picture, such as bladder cancer which is more likely to occur in older people rather than younger people.

(Jill Osborne) What are your thoughts on BCG??

(Dr. Theoharides) The published information is contradictory and we still don't understand why it would be helpful. We don't have a good theory yet on how it works. My feeling would be that one is more likely to try it on worse patients rather than milder patients.

(Jill Osborne) Lisa asks if it would be helpful to remove other allergens in our environment?

(Dr. Theoharides) I think that it would be helpful but might not necessarily reduce the same triggers that stimulate the bladder mast cells. I think what happens is the mast cells in IC patients become hypersensitive so that as the skin becomes more sensitive to environmental allergens, the bladder mast cells become more sensitive to other triggers some of which we don't understand but others we know are coming from neurons in the bladder.

(Jill Osborne) Are there any side effects to Algonot Plus?

(Dr. Theoharides) Nothing that we know so far and, individually, all of the components have been used for many years. A couple of patients, out of about 500 so far felt a little stomach upset when they took it on an empty stomach which might be the olive seed oil.

(Jill Osborne) Some patients have asked if they can take Algonot with chondroitin sulfate if they are allergic to sulfa drugs?

(Dr. Theoharides) The sulfa in the sulfa drugs is entirely different than in chondroitin sulfate so the answer is basically no. But, as I said earlier, the first time you take something you should be prudent.

(Jill Osborne) Do you think that Algonot would have to be taken indefinitely?

(Dr. Theoharides) In many cases with hydroxyzine we have found that after a few years patients could reduce the dose and some wean off it entirely.  I have the feeling, but not the evidence yet, that if the bladder is allowed to heal over a period of time Algonot could also be reduced. The ingredients in Algonot except for quercetin are natural parts of our body so there is no harm in taking it for a longer period of time.

(Jill Osborne) There are a lot of products on the market that entice IC patients and one popular approach is with citrus flavonoids, such as those found in many vitamin shops. They call them bioflavonoids. Any comments??

(Dr. Theoharides) I would stay away from anything that doesn't describe the particular flavonoid, such as quercetin for example. Better yet, ask what the purity of the quercetin might be. For instance, in Algonot, the purity is 99%. We reviewed the literature on hundreds of flavoinoids and published this a year ago. We found that only about five were useful to reduce inflammation where many others triggered inflammation. If any product does not indicate specifically what the flavonoid is, I would stay away because there have been many reports of patients taking citrus flavonoids, and their IC symptoms got worse.

Of the five, four useful flavonoids are not available. Only quercetin is, which is why we’re using it. We are actually in the process of getting a pure form of yet another one, which we think is better than quercetin.

(Jill Osborne) MOI asks if Algonot is a blood thinner like Elmiron?

(Dr. Theoharides) There are two publications that indicate that chondroitin does not have a blood thinning effect.

(Jill Osborne) Does glutamine have a place in clinical trials?

(Dr. Theoharides) The published reports show that glutamine has no effect.

(Jill Osborne) Folks... we'll stop here because Dr. Theo has given us an extra half hour and my fingers can't type much more! Dr. Theo is also donating several wonderful articles on IC that are PDF files.  including an article "Future Drugs for IC"

Purchasing Information:
Algonot Plus is now for sale in the ICN Marketplace & Shop

Related Links:
Algonot Plus – http://www.algonot.com
Algonot Information Sheet – http://www.ic-network.com/guestlectures/algonot.html
ICCTG Clinical Trials Group – http://www.ic-network.com/md/

Dr. Theoharides Contact Information:
T.C. Theoharides, M.D., Ph.D.
Professor of Pharmacology and Medicine
Tufts University School of Medicine
New England Medical Center
Boston, MA

Books & Resources That You can Purchase:
The Interstitial Cystitis Survival Guide By Dr. Robert Moldwin $13.00/$11.00 for ICN Subscribers

The necessary disclaimer: Active and informed IC patients understand implicitly that no patient, or website or presentation on a web site should be considered medical advice. We strongly encourage you to discuss your medical care and treatments with a trusted medical care provider. Only your personal provider can and should give you medical advice.

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