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REDUCING INFLAMMATION AND RESTORING BLADDER MUCUS
The Role of Quercetin, Glucosamine & Chondroitin

Speaker: Dr. Theoharis Theoharides, M.D. Ph.D.
Professor of Pharmacology and Experimental Therapeutics
Director, Molecular Immunopharmacology & Drug Discovery Laboratory
Sackler School of Graduate Biomedical Sciences, TUFTS University, Boston MA

Moderator: Jill Osborne, M.A. President & Founder
Interstitial Cystitis Network, Santa Rosa, CA USA
http://www.ic-network.com

Event Date & Description: November 2005 - ICN Guest Lecture Series

INTRODUCTION

Welcome everyone! If you have any doubt about the status of IC research, you should find great comfort in tonight’s lecture with one of the preeminent and passionate IC researchers in the world, Dr. Theoharis Theoharides. Dr. Theoharides has numerous patents and is interested in using natural molecules in food supplements for the treatment of allergic/inflammatory and malignant conditions (Related web site: Algonot.com). He is also interested in drug and biomedical research policy. He has served as the Clinical Pharmacologist of the Massachusetts Drug Formulary Commission continuously since 1986; he has also served on the Supreme Health Council, of the Ministry of Health, the HealthCare Board of the Ministry of Labor and Human Resources and the National Drug Organization of the Hellenic Republic (GREECE).

Dr. Theoharides has produced some of the most important research to date in IC, most notably the role of the mast cell, the use of antihistamines in treating IC and how stress can play a role in our condition. Tonight, Dr. Theoharides will be speaking more on the mast cell, the potential role of using bioflavonoids to treat IC and, of course, will take questions from the audience. Welcome Dr. Theoharides!

PRESENTATION

Jill Osborne: We’re going to begin this lecture with a little bit of anatomy. Clearly, IC involves the protective coating in the bladder, also known the GAG layer or mucus.  When that is disrupted a series of events of occur that creates more inflammation. Dr. Theoharides, please tell us about the GAG layer and mucus found in the bladder. Why is it important to us?

Dr. Theoharides: The wall of the bladder is protected by a layer of molecules called proteoglycans, those that contain both protein and sugar. This is another way of saying glycosaminoglycans (GAG). We can imagine these molecules as tails... free floating from the wall of the bladder and because they intertwine they create a layer which gives the impression of mucus. But it is not just mucus. This layer is made up mainly of two molecules, chondroitin sulfate and sodium hyaluronate. Due to their content of sulfur, they are negatively charged and they repel water. Therefore, they repel anything that might be in urine that could be noxious to the wall of the bladder.

Underneath the GAG layer are the cells that make up the first layer of the bladder, the urothelium. These are packed very tightly together and they do not allow anything to go through them, even if it got through the GAG layer. 

In IC and for reasons that we do not understand, both the GAG layer and the urothelium beneath the GAG layer may be disrupted. There is no specific cause that has been so far discovered for any such disruption. The trigger for the disruption could be coming from the urine or could be coming from inside the wall of the bladder due to a problem that exists in the body.

If it is from the urine, it could be noxious molecules or it could be repetitive small (subclinical) infections even though IC has never been associated with one type of a full blown infection. (In previous IC research studies, they looked in the urine and the biopsies of the wall of the bladder for any remnant of any infectious organisms, but none were found.) But, small continuous irritations from multiple urinary tract infections over the years could weaken this protective layer. 

The patient may have consumed certain foods or some medicines that can bind to the GAG layer and render it inactive. For instance, anything that might be very strongly positively charged will interact with the negative charges of the GAG layer and will neutralize the ability of the GAG layer to protect and then urine contents may then affect the wall of the bladder. One such molecule that both we and Dr. Parsons have used experimentally is protamine, which is positively charged. In both animals and humans, it will cause damage to the wall of the bladder.

Triggers that can come from the inside of the body can include activation of sensory nerve endings or inflammation due to an internal cause, not a cause due to urine. The reason why activation of sensory nerves is important is because these nerves arise from a certain level of the spinal cord and, at that level, other nerves converge from other parts of the body. For instance, nerves can be activated due to appendicitis, but may also stimulate nerves going into the bladder because they all originate in the same place in the spinal cord. Once the sensory nerves are activated, they release molecules that both induce inflammation in the bladder and can damage the bladder wall from the inside out.

In either case, we believe that a central cell for the initiation of the inflammation, whether it's from the bladder in, or the inside is the MAST CELL. Let's give an example of what happens if there is an insult from the bladder.  Let's call it... X.... will damage the GAG layer and get to the urothelial cells. The urothelial cells are not supposed to deal with any triggers. Once they feel the trigger, they send the message on to the SUBMUCOSA, the layer right behind the urothelial cell and very rich in nerves and mast cells.

In the submucosa, mast cells will immediately be activated and will release three sets of molecules that are very important in inflammation:

 1 – Histamine will make the blood vessels leaky. This will allow circulating white blood cells to come out of the vessel and into the tissue to take care of the offending molecule. This process makes the blood vessels swell up and create openings where the white blood cells can come out and enter the bladder to take care of the trigger. When you see inside the bladder with a cystoscope in many IC patients, the urologists see what are described as glomerulations, which are microhemorrhages. In other words, the dilation of the blood vessels (and through the blood vessels) both white cells and blood emerge thus creating the petechial hemorrhages that your doctor may see.

2 – Cytokines that make the wall of the blood vessels product “docking” areas (called vascular adhesion molecules) to which the circulating white blood cells attach and exit.

3 – Chemoattractants that draw circulating white blood cells to bladder tissues.

Jill Osborne: So, it's a defense mechanism??

Dr. Theoharides: Sometimes it is, but if the trigger is from the inside out as I described in the case of appendicitis, there is no real trigger because the inflamed appendix is in a different part of the body but the nerves to the bladder are tricked to think that there is also a problem in the bladder. Thus we have inflammation for no apparent reason. If the inflammation is allowed to continue, it damages the GAG layer and it sensitizes the nerves so much that they now become chronically irritated. This is what we call neuropathic pain, meaning pain just because the nerves keep on firing even though there may not be any reason for them to fire.

Now, based upon what we went through, any attempt to treat IC should aim to restore the GAG layer and reduce the inflammation. If we allow the latter to go on, the former may never be fixed. Both play a role in the overall pathophysiology of IC.

A more relevant example than appendicitis might be endometriosis. The inflammation in the peritoneal cavity where the endometrial tissue is found outside the uterus can irritate nerves that converge at the same part of the spinal cord as nerves that go to the bladder and vice versa. So, there is reason to believe that endometriosis could actually irritate the bladder through this mechanism. In a study that was published just last month by Dr. Stanford and his colleagues, it was shown that over 80% of patients who went to his clinic for possible endometriosis ended up having IC instead.

We obtained from him from both bladder and endometriosis biopsies.  In patients that had both conditions, we obtained biopsies from both sites in the body and we studied those biopsies. The findings were nearly identical whether it was endometrial or bladder tissue. There were three basic findings: (1) There was inflammation in both, (2) There was a very high number of activated mast cells and (3) A hormone that is released immediately under stress (Corticotropin-releasing hormone - CRH) was actually very highly expressed in both sites.

Our ongoing theory is that CRH released from local nerve endings, which could be either because of infection, trauma or emotional stress or such triggers.. can release CRH from local nerve endings and can activate the mast cells, which then generate the local inflammation. So our approach is to block either the release of the CRH from the nerves or prevent the CRH from activating the mast cells or block the release of noxious molecules from the mast cells. The latter seems to be easier for the time being and this can be accomplished fairly well, at least in the laboratory, with some select flavonoids, such as quercetin. A paper was published last month by us on exactly this last point in the British Journal of Pharmacology.

Kempuraj, D. et. al Flavonols inhibit proinflammatory mediator release, intracellular calcium ion levels and protein kinase C theta phosphorylation in human mast cells British Journal of Pharmacology (Aug 2005) 145:7 (934-944).

Jill Osborne: Let's talk about blocking the mast cells?

Dr. Theoharides: Flavonoids are naturally occurring compounds found only in plants. There are about 3000 of them in nature, seeds and green plants are particularly rich in them. It is due to the flavonoids that leaves change colors in the Fall. When the temperature drops the plants generate flavonoids to protect themselves. Different flavonoids are different colors. Quercetin, for example, is yellow.

Flavonoids have very potent antioxidant actions and they are also protective to the cells. Some of them have anti-inflammatory effects, and, as the research study and publication above clearly indicate, can block mast cells. It's important to understand that not all flavonoids can block the mast cell. For instance, out of about 25 flavonoids we studied only three were potent mast cell blockers. I stress this because some other flavonoids can actually irritate the mast cells. Therefore, I do not think it would be wise for any patient to buy anything that has a large collection of flavonoids, such as citrus, soy or bioflavonoids. As long as you have many flavonoids, you never know if you'll have a benefit or a detriment. A number of IC patients have told me that certain bioflavonoids were actually making their symptoms worse.

It is also very important for anyone using any dietary supplement to make sure that they know the purity and the source of the flavonoids. One reason why I am stressing this is that a few companies that sell quercetin get it from FAVA beans, but about 15% of Mediterranean extraction persons lack an enzyme to process it and if they ingest anything from FAVA beans they can have a reaction where their blood cells can be destroyed, a form of anemia called hemolytic anemia. In the Algonot line of products (Cystoprotek, etc.) quercetin is 99% pure from the Saphora plant and we're very proud of that.

Let's assume that a very pure quercetin can take care of the inflammation. This is not an immediate effect. It takes some time for all of the mast cells to be blocked which is why it takes 3 to 4 months of treatment before you can appreciate any benefit.

Now, let's go to the GAG layer. Since the GAG layer is made up of 50/50 Sodium Hyaluronate and Chondroitin Sulfate, it would make sense to give the body exactly those ingredients. Cystistat (from Bioniche) is actually Sodium Hyaluronate delivered into the bladder with a catheter. Cystoprotek contains both the Chondroitin and Sodium Hyaluronate in a capsule so that it can be given by mouth. Now... why should it be in a capsule and not a pill?

Chondroitin Sulfate in a powder cannot be absorbed easily from the gastrointestinal tract; in fact, less than 10% is absorbed. However, if you mix it with an oil it creates little spheres where the oil is the shell and powder is trapped inside and the whole little sphere is absorbed by the intestine.  These are called liposomes. Many companies use liposomes to deliver drugs effectively. We tested a number of oils for their ability to allow chondroitin sulfate to be absorbed more effectively.

Quercetin also cannot be absorbed very well because it likes lipid and does not dissolve in water. Therefore, the liposomes increase the absorption of both chondroitin sulfate and quercetin.  After testing about 7 different oils, we showed that Olive Kernel Extract gave us the best absorption. In fact, this extract also has unique anti-inflammatory properties that are synergistic with those of quercetin.

Basically, this extract is obtained by crushing the pits and leaves after the olive oil is produced by squeezing the “flesh” of the fruit. When these are crushed, you get the kernel extract. This is extremely rich in polyphenols such as what is found in red wine... and is supposed to be protective to the heart. Its consumption has been associated with great longevity in the southern part of Europe such as Italy or Greece. In fact, the olive kernel extract is imported from the island of Crete (Greece). So, not only are we increasing the absorption of the substances that will block the mast cells and heal the GAG layer, we're also providing something that is useful for health in general. This combination that I just described is covered by four US and one international patents and is known as Cystoprotek.

Jill Osborne: What was your motivating factor for creating a supplement for IC?

Dr. Theoharides: I've been studying IC for years with my former colleague Dr. Grannum Sant. I was very frustrated that there were no prescription drugs that were effective for IC. Those that were available, like Elmiron, were addressing the GAG layer partially. As you know, Elmiron is supposed to replenish the GAG layer. But, it is a very small synthetic sugar, meaning that it's not natural. Because it is small, it is washed out of the bladder very quickly. Moreover, a recent paper showed that only about 10% of Elmiron is absorbed when taken by mouth and it is even less likely to make it to the bladder. So, to me, it appeared reasonable to try to use the natural components of the GAG layer instead of a small synthetic molecule.

When I brought this interest to a couple of friends, one of whom I had helped medically, they suggested that a small company be formed to bring these ideas to fruition through a nutriceutical, thus founding our company Algonot. The name was chosen because it means NO PAIN. Algos, in Greek, means pain. Thus, Algonot means “NOT PAIN.” It’s like saying analgesic. 

I insisted from the beginning that this little company be as educational as possible so its website, http://www. algonot.com, tries to make articles available from me and other colleagues. It's the only company that I know in the world that states that if a person doesn't get any benefit by four months, they will return the money. So far, to my knowledge, we haven't had anyone return them except in a few cases where the bottle was damaged. I should also say that Cystoprotek can be taken with other drugs, including Elmiron.

The most important issue that I would like to raise, which also comes up all the time when people get in touch with me, is that many IC patients unfortunately have to take a lot of drugs, not only for IC but also other concurrent conditions. It is very difficult to answer patients when they ask "Can I take drug x, y, z together?" because many times drugs interfere with each other. So, it’s important for the patient, when they describe to the physicians what they are taking, to mention everything (including the supplements) because I know of other dietary supplements that could interfere with drugs..

One last point is that anytime there is inflammation in any organ, including the bladder, the surrounding muscles tend to tense up. Thus it’s important that the pelvic floor muscles be allowed to relax either through physiotherapy or through appropriate medications, such as a muscle relaxant. A little bit of valium can be helpful both for the anxiety associated with chronic disease and because it relaxes the bladder muscles.

In my mind, at this point in time, there is no ONE WAY to address the symptoms of IC. I'm a proponent of combining approaches as long as one physician is aware of all of them, so that you don't run the risk of one treatment opposing the other or making things worse.

Jill Osborne: Sonja asks "Why not make Cystoprotek an instillation?"

Dr. Theoharides: Technically, you can do it but there are two reasons why this hasn't been done.  (1) It is clearly preferable to give something by mouth because it is less invasive even if it takes longer to be effective. (2) The second is that anytime you put something in the bladder it is categorized as a medical device and it requires large clinical trials and FDA clearance. Algonot just doesn't have the funds to get this process through as much as we would like to.

Jill Osborne: Tlacey asks if her lower back pain could be the trigger for her IC?

Dr. Theoharides: Yes, both the stress of the work as well as your standing up for long periods of time could be aggravating the IC. Remember that both physical or emotional stress can trigger symptoms. If you're exposed to severe cold or heat this could provoke a flare. Also if you're under emotional stress, it can create more problems. The stimulation of the nervous  system releases CRH and other molecules from the nerve endings that aggravates the symptoms.

Jill Osborne: Do you support the use of DMSO in IC?

Dr. Theoharides: Firstly, we don't really understand how DMSO works or why it has to be given at 50% concentration. It is known, at that dose, that it can have anti-inflammatory effects. Some others feel that it also effects the nerve endings thus making them hyporesponsive (less responsive) for some period of time. Many patients experience pain after DMSO because it may cause many nerve endings to fire at once and exhaust themselves. The clinical studies have shown that any benefit doesn't last for more than a couple of months and most urologists do not use it as a first line therapy anymore. If a patient were to be seen to have a lot of inflammation on cystoscopy and biopsy, I tend to think that a few courses of DMSO might be helpful before one tries something else. But if there is little inflammation, I don't think it's helpful.

Unlike DMSO, there have been a number of intravesical cocktails. Dr. Whitmore was among the first to use such cocktails that include heparin, bicarbonate to change the pH (to make it less acidic), a little bit of steroid and, sometimes, an antibiotic. She had not published extensively about these cocktails, but Dr. Parsons recently picked it up and published two papers using heparin and bicarbonate with good results. The reason that heparin is being used is because it is very similar to chondroitin sulfate and much better than Elmiron, but you cannot use a lot of heparin because it is also a blood thinner. So, you could run the risk of the petechial hemorrhages in the bladder temporarily getting worse.

Jill Osborne: What are your thoughts on the use of botox and IC?

Dr. Theoharides: There have been four studies that I know of that investigated botox and IC. In theory, botox can inactivate sensory nerve endings and reduce pain. All the studies that were published were not double blind. In other words, there weren't any patients injected with normal saline. But, of these studies, two seemed useful and two not useful. I think a lot depends on who is doing the injections and where they are being done.

The nerve endings in the bladder overlap enormously and it’s not like you might inject botox in five nerve endings and you will take care of the pain because there might be another 150 that do the same thing. So, in the studies where there seemed to be a benefit, there were numerous sites injected in the bladder and it was mostly the pain that was reduced, not the other symptoms. For those IC patients with pain,  when other things have failed (such as Elavil, neurontin, or hydroxyzine) then botox may be useful.

Jill Osborne: Janie asks "What is your opinion of using hydroxyzine and other antihistamines for mast cells?"

Dr. Theoharides: It's an obvious question with a difficult answer. Firstly, in numerous studies about 40-60% of IC patients have some form of allergy or sensitivity. These patients should be taking an antihistamine for that problem alone because any flare up of these symptoms could also effect IC symptoms. However, in IC patients that do not have allergies, typical antihistamines such as Benadryl don't seem to help.

Hydroxyzine is unique because it has four actions. (1) It is an antihistamine, of course.  (2) It is also able to reduce anxiety. The word ATARAX is Greek and means to calm down. (3) It also blocks the release of histamine from mast cells (about 30% ). (4) When used in combination with opioid pain killers it creates better pain relief. There are many studies that compared morphine vs. morphine with hydroxyzine for pain or headache. The two used together were better than either one.

So, my initial recommendation for younger, newly diagnosed patients or those that haven't had symptoms more than a year or two, is to start with hydroxyzine at 25 mgs at night and build it up over a few months to 75 mgs at night together with Cystoprotek. If you only take hydroxyzine every now and then, it’s sedating. But if you take it every day, it's far less sedating.

Hydroxyzine is available in pill, capsule or as a liquid elixir. Atarax starts at 10 mgs, Vistaril at 25 mgs and the elixir starts at 5 mgs per teaspoon. As with Cystoprotek, you have to take it for 3 to 4 months. I do not recommend that it be used with anyone who has tremor in their hands because if you take more than 75 mgs per day, sometimes the tremor can get worse.

Jill Osborne: Do you have any new therapies under investigation?

Dr. Theoharides: Currently, all the clinical trials run under the IC Clinical Research Network (ICCRN) were negative. The only trial that gave good results was the trial for tricyclic antidepressant amitryptiline (Elavil). I'm excited for two reasons, one because of what I know and one because of what I don't know. What I know is that we can do much better than quercetin.  I already have two other candidate flavonoids which I am trying to find out how to produce in large quantities for the next formulation to come out. This might be in a year or so. I also know that we can increase the amount of the Chondroitin Sulfate and Sodium Hyaluronate, so the new formulation will have higher amounts.

What I don’t know but am still excited about is that I don't yet understand why IC occurs so more often in women. I don't understand why more money hasn't been dedicated to study if female sexual hormones have a role to play. I know from many patients that symptoms worsen around their menstrual cycle, just like migraines worsen at that time. Until we understand that process better, one may need to consider adding some of the newer birth control pills or the drug called lupron.

Jill Osborne: Dr. Theoharides, we thank you for so graciously giving of your time tonight. This information will help so many patients understand their IC and why various treatments can be helpful. Bravo!

Related Links:
Dr. Theoharides Research Laboratory - http://www.tufts.edu/sackler/pharmacology/faculty/theoharides/
Algonot Corporate Website - http://www.algonot.com
Purchase Cystoprotek, Algonot or Prostaprotek in the ICN Shop - http://www.icnshop.com

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