ICN Guest Lecture Series Transcript - April 21, 2003 (Review our Disclaimer)
Title: CystoProtek and ProstaProtek in Interstitial Cystitis and Chronic Prostatitis
Speaker: Dr. Theoharis Theoharides, Professor of Pharmacology & Internal Medicine, Tufts University, Boston MA.

Welcome to the ICN Guest Lecture Series. My name is Jill Osborne and I am the founder of the Interstitial Cystitis Network. It is my pleasure to be your host and moderator tonight. One of our goals for this lecture series is to bring the nations best resources directly into the homes and offices of IC patients in need. We have welcomed many of the brightest researchers and physicians in the IC world. Tonight, it my pleasure to welcome Dr. Theoharis Theoharides for the second time to our guest lecture series. Dr. Theoharides is one of the pre-eminent IC researchers and has played a critical role in the development of new therapeutic approaches for IC. His specialty has been the mast cell and how mast cells participate in bladder inflammation, especially in response to stress. Dr. Theoharides is appearing tonight to discuss two exciting events. The first is the big IC conference that was just held in Japan that brought researchers together from around the world to discuss IC and the development of new diagnostic criteria. The second is to discuss Algonot-plus plusand the two new dietary supplements that he has created - CystoProtek and Prostoprotek. Dr. Theoharides! Welcome back to the ICN! Tell us about the International Consultation on IC Japan. Many patients don't realize that IC is being diagnosed around the world!

Dr. Theoharides - This was a wonderful opportunity to meet clinicians, researchers and patient representatives from around the world in Kyoto, Japan to discuss the development of new diagnostic criteria for IC. It was extremely friendly and was in a forum that allowed discussion rather than just lecturing. The conference lasted for about five days. There were actually nine workshops during which a number of clinicians/researchers provided brief presentations of new findings on IC and then there was lively discussion as to how such findings contributed to the topic of the diagnosis. The workshops were very well organized with simultaneous translation that really impressed me as to how well done it was. I think I speak for everyone there! The translations were superb. One highlight of the conference was that it gave us all a chance to participate in every workshop so that everybody was fully informed. There were 9 specific workshops. Please note that the official results of the conference will be published in an upcoming issue of the International Journal of Urology. Therefore, I can't be specific as to our results, but I will give you some general thoughts.

The first workshop was dedicated to "What is IC?" We had patients and clinicians talk about IC and whether they felt that it was one or many disorders. The second workshop discussed "Research Criteria versus Clinical Criteria for diagnosing IC." The NIDDK criteria were considered too strict and should be used primarily for research studies. We discussed that the clinical diagnostic criteria to be used should be much more permissive and inclusive for the diagnosis of IC. The third workshop covered the "Pathology of IC." This was simple. Should we take a bladder biopsy for diagnosis of IC and, if so, what should we be looking for in the biopsy sample. There was general consensus that biopsies weren't necessary...but would be very useful for providing new insights in the pathophysiology of IC.

Jill O. - Moderator - The role of cystoscopy and hydrodistention has become controversial in the past few years. Many doctors no longer choose to do a hydrodistention as part of the diagnostic process for interstitial cystitis, despite it's use in the current NIDDK criteria for IC. Furthermore, and as we've discussed in several past lectures, there is considerable debate as to whether glomerulations are actually indicative of IC. One research study found that the procedure itself appeared to cause the small hemorrhages often correlated with IC. So, we do need some resolution about whether hydrodistention will continue to play such a strong role. Was this discussed in Japan? If so, what was the consensus of the participants???

The fourth workshop was dedicated to cystoscopy and hydrodistension. I think the only way that I can answer that is like it was mentioned for pathology above. It may not be required, but it can be useful. Hydrodistention does allow for a biopsy. One other issue that needs resolution is that many doctors use different liquids to distend the bladder, which can have effects on what they see during the cystoscopy. Some use water, some use normal saline, as well as a third liquid called isotonic glycine . There should be a consensus on what the appropriate medium/liquid should be because water (hydro-water in hydrodistention) is hyptonic and could cause damaged bladder mucosal cells to burst.

The fifth workshop covered the "The Role of Urodynamics" In other words, do we need to measure bladder capacity to make a diagnosis of IC? It would be fair to say that except in specific circumstances, it was felt that it is probably not required. The sixth workshop covered an essential research tool, the use of "Questionnaires to assess patient quality of life during IC research studies." We won't go into this tonight as there are at least two validated questionnaires, but additional ones are also used in clinical studies.

The seventh workshop covered "Current and Future Directions in Diagnostic Markers." The discussion basically centered on Susan Keay's work with the Anti Proliferative Factor (although she was not present) and a new possible biochemical profiling that I reported which was done in collaboration with a new company from Cambridge MA, called Cantata Pharmaceuticals. This, so far, can pick up with almost 100% accuracy IC from normal controls by doing a spot urine analysis. This means that this could be yet another new way of confirming a clinical diagnosis of IC perhaps before their symptoms become severe. We still need to conduct more specificity studies and to compare IC with other bladder diseases. Here is an outline of what I presented.

Title: Diagnosis of Interstitial Cystitis Using Biochemical Profiling
Topic: Current and future directions in diagnostic markers
Moderator: Suzan Keay
Names: Dong Wei¹, Lily Li¹, Arthur Rugg¹, Kojo Abdul-Hadi¹, Jim Rogers¹, Alexander Rosenberg¹, Steve Rounsley¹, Sean Sykes¹, Robert McCarroll¹, Mark Trusheim¹, Roger Wiegand, and William Boucher², Grannum R. Sant^{2, 3}, and Theoharis Theoharides^{2, 4, 5}
Address: ¹Cantata Pharmaceuticals, Cambridge, MA and ²Dept. of Pharmacology and Experimental Therapeutics, ³Dept. of Urology, ⁴Dept. of Biochemistry, ⁵Dept. of Internal Medicine Tufts — New England Medical School, Boston, MA, USA

Text: Interstitial cystitis (IC) is a painful bladder disorder, occurring mostly in women with an incidence of about 60/100,000. It is characterized by urinary frequency, nocturia and pelvic pain. Its "definitive" diagnosis has been difficult and has involved invasive, painful and expensive procedures, such as hydrodistention and cystoscopy of the bladder under spinal or general an anesthesia, with or without biopsy, or intravesical administration of a high potassium concentration. We have developed a liquid chromatography/mass spectrometry platform capable of analysis of up to 200 analytes in a 10-minute assay. The set of analytes measured covers a broad range of compounds including amino acids, nucleotides, sugars, organic acids, and inflammatory mediators. We have also developed algorithms that permit these profiles to be analyzed for signature subsets of changes that correlate strongly with biological processes. Using linear discriminant analysis we compared spot urine from patients with confirmed diagnosis of IC to urine from normal healthy volunteers. We found that 23 biochemicals made a significant contribution to a biochemical signature that strikingly distinguished IC from normal urine (many log separation, p<0.05 with multivariant analysis).Based on leave-one-out cross validation, the resulting signature correctly classified 35 of 36 samples, a call rate of approximately 97%. Blinded validation and specificity testing are in progress. It is clear that there are substantial alterations in the biochemical composition of urine between IC and normal patients that have the potential of becoming the basis of a rapid, convenient and noninvasive diagnostic test for IC.

We will know next month if this as as promising as we think it is. A grant application was submitted jointly by the company and myself for exactly this reason. I'm very excited about this possible new breakthrough. By the way, this test is not based on mast cells, unlike my previous work. This is a more a test which creates a biochemical profile of the urine of IC patients. This is exciting to me as a researcher because these biochemicals might lead me and others to yet more findings about what causes IC.

The eighth workshop covered "Future research needs for the definition/diagnosis of IC." We mostly spoke about the fact that it makes sense to add "interstitialcystitis/chronic pelvic pain syndrome" rather than just calling IC... IC. The last workshop was "Is IC an autoimmune disease?" - There was discussion about many other conditions that coexist in IC patients, such as fibromyalgia, IBS, Sjogren's, allergies, migraines. Even though one could not call IC autoimmune as such, clearly there was a feeling that there had to be some systemic effects over and beyond just bladder symptoms. In other words, that there may be a impact throughout the body, or something more systemic but that has a larger expression in the bladder.

Jill O. - Moderator - Dr. Theoharides, I'm not sure if the newly diagnosed patient understands just how important meetings like these are. There has been so much varying research, varying beliefs, and varying methods of treating IC here in the USA. We also see significant variations and disagreements between physicians in many different nations. There is no doubt that IC is being diagnosed (or misdiagnosed) in many different ways throughout the world. So, just the fact that an international group of researchers and physicians spent time trying to create consensus was a first for the IC community. What's the next step after the Japanese conference?? Are there any additional conferences and/or meetings to occur. When can we some resolution to these important questions.

Dr. Theoharides - I agree wholeheartedly with you and it was amazing to see specialists disagree about some things, but then reach an agreement about others. If we disagree.... imagine how much more difficult it is for the patients. By the same token, the fact that we pretty much agreed on the most important points will make both diagnosis and treatment of patients easier in the future.

First, there will be an NIDDK Bladder Symposium conference in late October 2003 in Washington DC, where the outcome of the meeting in Kyoto will be presented. Hopefully, we can iron out some minor differences that were left hanging in the breeze. Secondly, there will be another International conference about 2 years from now... most likely in Southern Europe where we hope to have a formal agreement on new diagnostic criteria and emphasize international clinical trials, rather than just US based trials. Hopefully, the next meeting will focus more on treatments rather than diagnosis.

Jill O. - Moderator - We are so proud of the patients and researchers who have put this conference together. Our congratulations to the Japanese physicians and IC group (Tomo No Ki) for hosting the event and for IICPN member Jane Meijlink (Holland) who did a massive amount of work making this happen. Jane is an IC patient just like everyone in this room and yet she has a global impact. She is the perfect example of how an IC patient can truly make a difference! Let's change gears now and talk about Algonot-plus and your new products CystoProtek/Prostoprotek. In your last lecture, you talked extensively about the use of quercetin, glucosamine and chondroitin sulfate (ingredients of Algonot-plus-plus). Why have you come up with a new product??

Dr. Theoharides - There are a number of reasons. I always listen to what patients say. I also try to incorporate research findings and new ideas for treatment. The comments from the patients so far have been very supportive for our first product, Algonot-plus-plus. So far, there has been a 97% reorder rate from IC patients and practically every email we have received has been indicative of some benefit, which can vary depending upon the severity of the symptoms.

The two issues that we had to address about Algonot-plus-plus were that the capsules were fairly large and that some patients were not used to olive oil and it gave them some burping and gas. For the second, I suggested that patients increase the number of capsules slowly over 2-3 weeks, starting with 2 capsules for a few days, then 4 capsules for a few weeks, and then eventually 6 capsules a day. It also helps to keep the bottle in the refrigerator and even freeze the capsules before swallowing them because that also makes the swallowing easier. This has worked in everyone that I've spoken with. With respect to size, we tried to reformulate the ingredients so that we could put them in a smaller capsule and we managed to do that. In fact, both CystoProtek and ProstaProtek are in a smaller capsule.

As long as we were doing this, I also tried to incorporate new research findings. The findings over the last two years centered on sodium hyaluronate (SH). The protective lining of the bladder is made up what we call the GAG (glycosaminoglycans). This layer is made of two components, which are sort of intertangled with each other. One is chondroitin sulfate and the other is sodium hyaluronate (SH). One major difference between the two is that chondroitin in sulfated and sodium hyaluronate is not. It was shown that sodium hyaluronate was increased in the urine of IC patients and it was increased more than other sulfated gags which meant that the bladder of IC patients was losing this protective sodium hyaluronate more than other components.

There were three studies published in the last year. One clinical study gave SH intravesically into the bladder in IC patients and about 1/3 of them got better. The other study that we did involved rats. We found that by protecting the bladder with SH before causing bladder irritation, appeared to protect the bladder from irritation. In another study, the SH seemed to help increase the healing of the bladder mucosa. These were significant enough in my mind to see if we could incorporate SH in the new formulations. The obvious question was if SH can be taken by mouth?

There were three sets of findings that told us that it could. Firstly, a program on ABC 20/20 "The Village of Long Life" was broadcast on November 2, 2000. It was about a small village in Northern Japan where the diet is very rich in SH. Citizens were apparently living unusually long lives, often more than 100 years of age. It appeared that SH seemed be an antiaging remedy. So, obviously, atleast in this village, they were consuming it by mouth and lots of it. The second set of findings was that, for many years, they have used SH in horses and dogs by mouth to reduce inflammation, especially in the joints and, in fact, there are two well known companies in the US that sell a preparation for animals. Oral SH has been used by mouth for many years without problems for

• Painful conditions in veterinary medicine (e.g. "LUBE-ALL" (http://www.equiaide.com/doglubeall402.htm)
• Painful oral lesions "Gelclair" (http://gelclair.co.uk/)
• Skin Health "Injuv" (http://www.coqsol.com/injuv/)
• Longevity "Ultimate HA" (http://www.purityproducts.com)

The third involves tempomandibular joint disorder (TMJ). There have been five clinical trials that I know where they gave oral SH with very good results for TMJ.

• Guarda-Nardini L, Tito R, Staffieri A, Beltrame A. Treatment of patients with arthrosis of the temporomandibular joint by infiltration of sodium hyaluronate: a preliminary study. Eur Arch Otorhinolaryngol 259:279-84, 2002.
• Bertolami C, Currie R. Sodium hyaluronate for TMJ disorders. Aust Dent J 40:399, 1995.

So, obviously, SH has been used both in humans and animals for a couple of conditions with few, if any, problems. Morever, SH by mouth has higher absorption than chondroitin sulfate. So, we decided to obtain SH from probably the best company in the world that makes it for medicinal purposes, Seikagaku Corporation (Japan). They actually make it for intravesical administration (Cystistat by Bioniche, Canada) and for intra-articular injection into the joints for osteoarthritis patients (Supartz).

References on the intravesical use of SH

• Leppilahti M, Hellstrom P, Tammela T. Effect of diagnostic hydrodistension and four intravesical hyaluronic acid instillations on bladder ICAM-1 intensity and association of ICAM-1 intensity with clinical response in patients with interstitial cystitis. Urology 60:46-51, 2002.
• Boucher WS, Letourneau R, Huang M, Kempuraj D, Green M, Sant GR, Theoharides TC. Intravesical sodium hyaluronate inhibits the rat urinary mast cell mediator increase triggered by acute immobilization stress. J Urol 167:380-4, 2002.
• Takahashi K, Takeuchi J, Takahashi T, Miyauchi S, Horie K, Uchiyama Y. Effects of sodium hyaluronate on epithelial healing of the vesical mucosa and vesical fibrosis in rabbits with acetic acid induced cystitis. J Urol 166:710-3, 2001.
• Nordling J, Jorgensen S, Kallestrup E. Cystistat for the treatment of interstitial cystitis: a 3-year follow-up study. Urology 57(6 Suppl 1):123, 2001.
• Wei DC, Politano VA, Selzer MG, Lokeshwar VB. The association of elevated urinary total to sulfated glycosaminoglycan ratio and high molecular mass hyaluronic acid with interstitial cystitis. J Urol 163:1577-83, 2000.
• Morales A, Emerson L, Nickel JC. Treatment of refractory interstitial cystitis. Int Urogynecol J Pelvic Floor Dysfunct 7:215-20, 1996.
• Erickson DR, Sheykhnazari M, Ordille S, Bhavanandan VP. Increased urinary hyaluronic acid and interstitial cystitis. J Urol 160:1282-4, 1998.
• Porru D, Campus G, Tudino D, Valdes E, Vespa A, Scarpa RM, Usai E. Results of treatment of refractory interstitial cystitis with intravesical hyaluronic acid. Urol Int 59:26-9, 1997.
• Morales A, Emerson L, Nickel JC. Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis. Urology 49(5A Suppl):111-3, 1997.
• Morales A, Emerson L, Nickel JC, Lundie M. Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis. J Urol 156:45-8, 1996.

With respect to the specific formula of CystoProtek/Prostoprotek, we did make a change. We reduced the amount of glucosamine present in Algonot-plus-plus by 20 mgs and substituted 20 mgs of sodium hyaluronate instead. So, if you were to be taking 6 capsules a day, that would be 120 mgs a day which is 3x more than what they used when they gave SH intravesically. Preliminary studies that we've done, at least in animals, show that about 30% of SH gets absorbed in the bloodstream.

Because a lot of patients have been taking Algonot-Plus and because CystoProtek is very similar, I feel that patients should continue to take Algonot-Plus and, depending upon how severe their symptoms have been, to add CystoProtek in small amounts. For example, if a patient takes 4 capsules a day of Algonot-plus, they could add 2 or 4 capsules of CystoProtek. That way no one will have to stop the Algonot-plus, but they can still get the benefit of the SH in a smaller capsule.

Algonot-plus-plus, CystoProtek and ProstaProtek is protected by 3 US patents and work related has been published in major scientific journals as follows:

• Theoharides, T.C. and Sant, GR. A pilot,clinical trial on the use of Algonot-plus-plus in interstitial cystitis. Int J Immunopathol Pharmaco, in press.
• Theoharides TC, Alexandrakis M, Kempuraj D, Lytinas M. Anti-inflammatory actions of flavonoids and structural requirements for new design. Int J Immunopathol Pharmacol 14:119-127, 2001.
• Theoharides, T.C., Kempuraj, D. and Sant, G.R. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology 57 (Suppl 6A): 47-55, 2001.
• Middleton E Jr, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 52:673-751, 2000.
• Theoharides TC, Patra P, Boucher W, Letourneau R, Kempuraj D, Chiang G, Jeudy S, Hesse L, Athanasiou A. Chondroitin sulphate inhibits connective tissue mast cells. Br J Pharmacol 131:1039-49, 2000.
• Chiang G, Patra P, Letourneau R, Jeudy S, Boucher W, Green M, Sant GR, Theoharides TC. Pentosanpolysulfate inhibits mast cell histamine secretion and intracellular calcium ion levels: an alternative explanation of its beneficial effect in interstitial cystitis. J Urol 164:2119, 2000.
• Theoharides TC, Letourneau R, Patra P, Hesse L, Pang X, Boucher W, Mompoint C, Harrington B. Stress-induced rat intestinal mast cell intragranular activation and inhibitory effect of sulfated proteoglycans. Dig Dis Sci 44(8 Suppl):87S-93S, 1999.
• Alexandrakis M, Singh L, Boucher W, Letourneau R, Theofilopoulos P, Theoharides TC. Differential effect of flavonoids on inhibition of secretion and accumulation of secretory granules in rat basophilic leukemia cells. Int J Immunopharmacol 21:379-90, 1999.
• Trnovsky J, Letourneau R, Haggag E, Boucher W, Theoharides TC.Quercetin-induced expression of rat mast cell protease II and accumulation of secretory granules in ratbasophilic leukemia cells. Biochem Pharmacol 46:2315-26, 1993.

Moreover, Algonot-plus-plus, CystoProtek and ProstaProtek contain kernel olive oil that increases the absorption of the active ingredients and provides additional anti-oxidant and cytoprotective molecules, while having anti-inflammatory action of its own. For those who would like to research the benefits of kernal olive oil further, here is a list of key references:

• Skoldstam L, Hagfors L, Johansson G. An experimental study of a Mediterranean diet intervention for patients with rheumatoid arthritis. Ann Rheum Dis 62:208-14, 2003.
• Kjeldsen-Kragh J. Mediterranean diet intervention in rheumatoid arthritis. Ann Rheum Dis 62:193-5, 2003.
• Martinez-Dominguez E, de la Puerta R, Ruiz-Gutierrez V. Protective effects upon experimental inflammation models of a polyphenol-supplemented virgin oil diet. Inflamm Res 50:102-106, 2001.
• Alarcon de la Lasra C, Barranco md, Motilva V, Herrerias JM. Mediterranean diet and health: biological importance of olive oil. Curr Pharm Des 7: 933-950, 2001.
• Martinez-Dominguez E, de la Puerta R, Ruiz-Gutierrez V. Protective effects upon experimental inflammation models of a polyphenol-supplemented virgin olive oil diet. Inflamm Res 50:102-6, 2001.
• Kremer JM, Lawrence DA, Jubiz W, DiGiacomo R, Rynes R, Bartholomew LE, Sherman M. Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Clinical and immunologic effects. Arthritis Rheum 33: 810-820, 1990.

I need to stress is that it may take at least 3-4 months for improvement of the underlying condition and reduction of symptoms. Some patients report that they get better in a few weeks, but I really believe patients should try it for up to 6 months if possible. I don't think that they would get the benefit that one would expect by only taking it a few weeks.

Jill O. - Moderator. What is Sodium Hyaluronate made from?? Since patients now have a choice between Algonot Plus and Cystoprotek, how should they choose? Is there a plan for a patient already using Algonot to transition over to Cystoprotek? Can they be used together???

Dr. Theoharides - Sodium hyaluronate is made from chicken combs. So, if a patient is sensitive to eggs, they have to be careful. Any product containing sodium hyaluronate may potentially cause an allergic reaction, but the published evidence so far has not reported such reactions. It is always wise to consult with your health provider first. I take pride in making sure what the source and all of the ingredients are listed. This is something that the federal trade commission will be insisting on later this year. I've always believed that patients and their health care providers should know what is exactly in the supplement. This is NOT commonly done with other dietary supplements and it makes it very difficult to know what one is taking and to compare it.

I need to stress that it is critical to now the EXACT content and source of what one consumes (look at the Table attached). For instance, Cysto-Q and Prosta-Q, as well as many other dietary supplements, claim a proprietary formula and do not list either the amount or source of the contents. This is a serious problem because there may be adverse effects and interactions that make it impossible to know if such products can be combined with others that may have the same active ingredients. For instance, quercetin is commonly obtained from fava beans. This is important because about 15% of Mediterranean extract people lack the enzyme G6PD and could get serious anemia (hemolytic) if they eat fava bean related material, but the consumer is unaware of this danger because the source is not listed in other products. Instead, Algonot-plus, CystoProtek and ProstaProtek obtain quercetin from the Saphora plant.

Two important articles of ours discuss dietary supplements for inflammatory conditions, including IC. One was just published in the European Journal of Inflammation and this will be available on our (and the ICN's) website for you to review for free! The second paper is based on an invited lecture I gave last October in San Antonio TX at an international conference on Alternative medicine sponsored by the National Institutes of Health and by the American Academy of Allergy, Asthma and Immunology. I was invited to have that published in the Annals of that academy and it will show up in early fall. It was very gratifying that many other colleagues on other disciplines were listening to scientifically based dietary supplements.

• Theoharides TC. Dietary supplements for arthritis and other inflammatory conditions: key role of mast cells and benefit of combining anti-inflammatory and proteoglycan products. European J Inflamm 1:1-8, 2003.
• Theoharides TC. Dietary supplements for inflammatory conditions and the role of mast cels. Annals Allergy, Asthma, Immunol, in press.

I would suggest that NEW patients start with CystoProtek. If patients find Algonot-plus too big to swallow, then they may switch to CystoProtek because it is a smaller capsule The quality and the source of the ingredients in both is exactly the same.

Here's is some other important news! There was a request for applications from the Department of Defense this month for which I submitted a large application to conduct a randomized, double-blind, placebo-controlled, clinical trial where we will be using CystoProtek in 80 patients with IC and 80 patients with chronic prostatitis to be done at the McDill Air Force base in Tampa, FL with Dr. Swana. We will be using two questionnaires for symptoms, as well as the biochemical profiling that I discussed earlier at the beginning and at the end of this study. Our hope is threefold. (1) To show how helpful CystoProtek may be so that clinicians will find it easier to adopt it; (2) To generate results as to whether it will also be helpful for prostatitis, as well as IC; (3) To investigate if the urine biochemical profiling can show an improvement in symptoms.

Jill O. - Moderator - Dr. Theo... I'm absolutely floored that you're doing a study with the Air Force. We struggle with many active military members who have IC who have had a difficult time getting medical care. It appears that many military medical personnel just don't know what IC is or how to treat it. From enlisted men to command staff, IC can seriously impact their careers. One of my pet projects has been to promote IC awareness among military medical facilities. Given the state of war, and the tremendous stress that so many patients have been under, it doesn't surprise me that we have a significant number of patients in the military. What is your take on stress and IC?

Dr. Theoharides - Firstly, there has been at least one published study where they showed that enlisted personnel had a much higher incidence of pelvic pain during missions. One study was during United Nations missions abroad. There have also been two studies where they showed that stress increased IC symptoms in IC patients just in the last year and a half. There has also been reports that stress worsens IC symptoms and promotes mucosal infections:

• Drabick JJ, Gambel JM, Mackey JF. Prostatodynia in United Nations peacekeeping forces in Haiti. Mil Med 162:380-3. 1997.
• Soderholm JD, Yang PC, Ceponis P, Vohra A, Riddell R, Sherman PM, Perdue MH. Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine. Gastroenterology 123:1099-108, 2002.
• Lutgendorf SK, Kreder KJ, Rothrock NE, Ratliff TL, Zimmerman B. A laboratory stress model for examining stress and symptomatology in interstitial cystitis patients. Urology. 57(6 Suppl 1):122, 2001.
• Rothrock NE, Lutgendorf SK, Kreder KJ, Ratliff TL, Zimmerman B. Daily stress and symptom exacerbation in interstitial cystitis patients. Urology 57(6 Suppl 1):122, 2001.

We have done three studies where we induced stress in rats and mice (mild stress by keeping them in a Plexiglass immobilizer for up to 2 hours). We found out that the amount of urine put out increased tremendously and that the bladder became inflamed within two hours.

• Theoharides, T.C. Mast cells and stress: A psychoneuroimmunological perspective. J. Clin. Psychopharmacol. 22:103-8, 2002.
• Alexacos N, Pang X, Boucher W, Cochrane DE, Sant GR, Theoharides TC. Neurotensin mediates rat bladder mast cell degranulation triggered by acute psychological stress. Urology 53:1035-40, 1999.
• Spanos C, Pang X, Ligris K, Letourneau R, Alferes L, Alexacos N, Sant GR, Theoharides TC. Stress-induced bladder mast cell activation: implications for interstitial cystitis. J Urol 157:669-72, 1997.

And, we (Dr. Sant and I) just got word from the NIH that we got a very large grant funded starting in July to study this as another animal model for IC, using various genetically deficient mice, and how to block it. We're very excited about this. {1 R01 DK062861 NIDDK (PI: Theoharides) Duration: 5/1/03-4/30/07 Acute restraint stress-induced neurogenic bladder inflammation Direct Cost/year: $175,000 plus Indirect Cost/year: $75,000. Entire grant award: $1,000,000}

We have also identified from other studies that the hormone that we thought is only released in the brain during stress is ALSO released in the bladder during stress and that contributes to the inflammation by triggering the mast cells. In fact, we found out the exact same thing happens in the uterus of patients who have spontaneous miscarriages. That will be appear in the April issue of "Endocrinology." In fact, I will be curious to know if IC patients may have had more spontaneous miscarriages than others. Maybe that's a question Jill can ask in the ICN Survey Center.

• Madhappan B, Kempuraj D, Christodoulou S, Boucher W, Tsapikidis S, Karagiannis V, Athanassiou A, Theoharides TC. High levels of intrauterine corticotropin-releasing hormone, urocortin, tryptase and interleukin-8 in spontaneous abortions. Endocrinology 144:2285-2290, 2003.

------------------- Audience Question & Answer Session Begins -------------------

#1 Lisa asks "what do you think of pudendal neuralgia?"

Dr. Theoharides - I'm fairly convinced that there is neuralgia in IC. Whether it is pudendal or more localized in the bladder, it's almost impossible to tell. However, in an animal study that was published some years back they stimulated electrically the nerve that leads to the pudendal nerve and they caused inflammation in the bladder. I think that inflammation of the nerve is going to cause bladder inflammation and then the bladder inflammation makes the nerves hypersensitive, which then creates a cycle of inflammation. The products (Algonot-plus, CystoProtek) that we discussed are only likely to help the second part. By reducing the inflammation in the bladder, we can reduce the stimulation of the nerves. We can reduce the stimulation from the "bottom up." But, once the nerve has become hypersensitive, you need additional treatment. One of the approaches is Neurontin. Neurontin (gabapentin) was primarily developed as a seizure medication. With this medication, we can bring their nerves down to baseline normal function.

Some of the older tricyclic antidepressants such as Elavil (amitriptyline) or Sinequan (doxepin) can also be used to reduce this hypersensitivity in nerves. They have been also used effectively after herpes zoster Neuralgia. But these are sedating and some people can't tolerate them. Most recently, for those nerves that are exposed in the bladder, there have been efforts to do clinical trials using some drugs that deplete the nerve endings of molecules that cause pain, such as Substance P. I think we will see results from these trials in the next year or so.

• Theoharides, TC and Sant, GR. Neuroimmune connections and regulation of function in the urinary bladder. In Autonomic Neuroimmunology (J. Bienenstock, E. Goetzl and M. Blennerhasset, eds.). The Autonomic Nervous System (Series Editor: Geoffrey Burnstock), vol. 15:345 — 369. Harwood Academic Publishers: Reading, 2003.
• Theoharides TC, Sant GR. New agents for the medical treatment of interstitial cystitis Expert Opin Investig Drugs 10:521-46, 2001.

#2 Brat asks "If, as a mother with IC, if her daughter will also develop IC?"

Dr. Theoharides - A short paper was published by Dr. Warren where he identified sets of identical and fraternal twins and he found out that only the identical twins had IC. So, even in fraternal twins, the likelihood that both would have IC is very small. Given that there have been certain families identified with multiple female members with IC there might be a slight increased chance of the female member developing IC, but it is certainly not definite. With the help of a urologist from Europe, Dr. Jordan Dimitrikov, who published a paper on a cluster of IC in a family, we have access to 15 families with identical twins with IC in Europe. Last January, we submitted an application to the NIH to carry out genetic analysis and biochemical profiling of these patients and we're waiting to hear if this study get funded.

#3 Peiti asks a great question about diet. "Does eating acidic foods or bad foods, even when we're feeling okay, cause more inflammation?? Should we follow the diet even when we're not in a flare??"

Dr. Theoharides - The first part of the answer is that diet varies from person to person. You cannot generalize because we're all individual...and we have different food tolerances. So, it would be fair to say that if foods bother you, yes eating those foods could cause more irritation. One reason is that if the bladder has not healed completely, you'll be irritating raw wounds. Second reason is that many food substances directly stimulate nerves themselves. We know that because certain foods, such as wine bothers many IC patients. Wine also brings about migraines in many patients. In fact, we've had a number of patients that did so well on Algonot-plus that they started eating spicy foods! The answer is that you can't over do it. We're struggling to make the bladder heal. By the same token, if you'd like to try something mild, you can find your limit of tolerance. Just don't push your luck!

#4 Burning asks "How does DMSO works.. especially if it burns us?"

Dr. Theoharides - Firstly, no one knows how DMSO works. Two studies have shown that DMSO depletes the nerve endings and the mast cells of the bladder by causing a massive release of the molecules that cause pain and inflammation. Then it takes weeks for them to get replenished. So, I believe that the burning is because it causes this massive release of the molecules from mast cells and nerves. The benefit is that over a few weeks to a month, there aren't those molecules there to contribute to inflammation until they get restocked/regrown again. One approach that I have suggested is to give DMSO with a local anesthetic at the same time, so that the anesthetic will reduce the burning. Dr. Whitmore uses a local anesthetic in her intravesical "cocktail." One relevent study is:

• Birder LA, Kanai AJ, de Groat WC. DMSO: effect on bladder afferent neurons and nitric oxide release. J Urol. 158:1989-95, 1997.

#5 Dixie says that she's had many UTIs since she was a child. "Could having repeated UTI's contribute to developing IC?"

Dr. Theoharides - I definitely think so. For two reasons. One is that anytime we have a UTI, it causes some damage and inflammation to the bladder and many patients who have frequent UTIs may also have a subclinical infection in-between (i.e. a small amount of bacteria that would not cause a UTI). There have been papers published over the last few years where they showed that just a few bacteria (that would never cause a clinical UTI) can still attach to a mast cell and cause the release of histamine and other noxious molecules. Moreover, bacteria such as E. coli and S. aureus have been shown to activate mast cells through specific mast cell surface receptors. If you're interested in reading more, here are some relevent papers:

• McCurdy JD, Olynych TJ, Maher LH, Marshall JS. Cutting edge: distinct Toll-like receptor 2 activators selectively induce different classes of mediator production from human mast cells. J Immunol 170:1625-9, 2003.<
• Marshall JS, King CA, McCurdy JD. Mast cell cytokine and chemokine responses to bacterial and viral infection. Curr Pharm Des 9:11-24, 2003.
• Brzezinska - Blaszczyk E, Wasiela M. Vaginal bacterial flora activates rat peritoneal mast cells. Int J Immunopathol Pharmacol 15:233-238, 2002.
• Malaviya R, Ross E, Jakschik BA, Abraham SN. Mast cell degranulation induced by type 1 fimbriated Escherichia coli in mice. J Clin Invest 93:1645-53, 1994.

So, in that case, you have inflammation even though you don't have a UTI. Moreover, both we and Dr. Saban have used only part of the surface of bacteria, called LPS, in the bladder of mice and we caused inflammation of the bladder. This means that you don't have to have a full blown infection to cause bladder problems. My feeling is that repetitive damage to the bladder, either due to full UTIs, or a subclinical UTI, or material left over from even dead bacteria might contribute to inflammation. That doesn't mean that someone will get IC, but my gut feeling is that it will definitely contribute.

#6 Gabby want to know where she can get the CD you talked about?

Dr. Theoharides - Just call Denise Hyman at: 941-346-5304 and she'll mail one to you!

#7 AB asks "Is IC and prostatitis are pathophysiologically identical, since it also appears that they have identical symptoms?"

Dr. Theoharides - To the extent that we don't know exactly what IC is, it's impossible to say that they are identical. However, I believe that they are very similar or different expressions of the same underlying problem. This is why we're trying to do these studies with both IC and prostatitis so that we can compare the two more completely. We were the first to publish a paper in the International Archives of Allergy and Applied Immunology in 1990. It was the first report to my knowledge of a male patient that had both problems.

I believe that they may have the same pathophysiology, but there are reasons why women may have more IC symptoms. #1. We, and others, have published that high levels of estrogen make inflammation worse. Many patients say that their symptoms get worse around ovulation. #2. During puberty, when testosterone gets high, testosterone has been shown to reduce inflammation so there may be an innate difference between men and women due to hormones.

• Theoharides TC, Flaris N, Cronin CT, Ucci A, Meares E. Mast cell activation in sterile bladder and prostate inflammation. Int Arch Allergy Appl Immunol 92:281-6, 1990.
• Pang X, Cotreau-Bibbo MM, Sant GR, Theoharides TC. Bladder mast cell expression of high affinity oestrogen receptors in patients with interstitial cystitis. Br J Urol 75:154-61, 1995.
• Vliagoftis H, Dimitriadou V, Boucher W, Rozniecki JJ, Correia I, Raam S, Theoharides TC. Estradiol augments while tamoxifen inhibits rat mast cell secretion. Int Arch Allergy Immunol 98:398-409, 1992.

#8 "Does IC have a connection with Reflex Sympathetic Dystrophy"

Dr. Theoharides - Yes, that's a medical term for when nerves get sensitized...See above discussion!

#9 "Do you have any thoughts about Aloe Vera and IC?"

Dr. Theoharides - There has not been any publication with IC specifically...however there have been a few publications, although not in the best scientific journals, that aloe vera can reduce inflammation. One publication that was of great interest to me is that it also inhibits mast cells. So, my take is that it probably doesn't hurt to take it. After all, most cosmetic products have aloe vera for the skin. The only thing I would like to stress is that, if at all possible, one should use a source where the purity is well known. Many IC patients are so sensitive, they may respond adversely to bi-products found in unpurified preparations of Aloe!

• Ro JY, Lee BC, Kim JY, Chung YJ, Chung MH, Lee SK, Jo TH, Kim KH, Park YI. Inhibitory mechanism of aloe single component (alprogen) on mediator release in guinea pig lung mast cells activated with specific antigen-antibody reactions. J Pharmacol Exp Ther 292:114-21, 2000.

#10 Lisa asks "Can constant pus in their para-urethal glands along the urethra contribute to some neuroinflammation??"

Dr. Theoharides -

Yes! Unlike the nerves that go to our fingertips that have very distinct connections along the spinal cord and to the brain, the nerves that go to the pelvic area are very diffuse. This means that the nerves that go to the peri-urethral area may go to a certain level to the spinal cord, but also to two or three levels up and down. This means that any other nerves that come out from those other levels of the spinal cord will also be activated. Inotherwords, you can have a nerve from the periurethral area that could induce pain elsewhere, such as in the abdomen or in the rectal area.

There are two things that one might be able to do. #1. Find out why the pus and infection is there! Sometimes one can even inject antibiotic directly into those areas rather than giving it by mouth. If you get repetitive infections, the tissue may become fibrotic thus reducing blood flow so oral antibiotics can't get there. Therefore, an injection into that cavity or gland might be one approach. #2 would be to treat the problem just like someone had sciatica. What they do is actually inject a steroid with a local anesthetic right into the spinal chord where that pain originates. Usually a specialized anesthetist can do this and that could take care of the problem for some months up to a year.

#11 Sandie asks "Why does an IC patient often experience the IC belly.. the generalized swelling of the lower abdomen...that so many of us have found so frustrating?" "Why does it suddenly go away?"

Dr. Theoharides - A possible explanation is that the beginning of inflammation always involves what we call increased vascular permeability, which means that the blood vessels dilate and become leaky. The first thing that happens is that a lot of fluid comes out of the blood vessels and into the tissues. Then what happens is leukocytes/white blood cells come out and that might also set up inflammation. So, to the extent that the blood vessels become leaky, alot of fluid will come out and cause the "IC belly".

The dilation of the blood vessels doesn't last a long time. To the extent that we discussed earlier, nerve endings come to the different parts of the spinal cord. This will make different parts of the abdomen swell up. In this problem a drug like Atarax could possibly be helpful because the primarily molecule that causes the swelling is histamine. One of the more effective therapies for IC is the use of antithistamine, but it's a unique antihistamine - hydroxyzine (ATARAX OR VISTARIL). It is unique because it has four properties:

• Antihistamine
• Anticholinergic (reduces the urge to urinate)It is sedating (reduces nocturia)
• Slightly anti-anxiety (but not as good as valium) Atarax, in greek, means to calm down
• It blocks mast cell activation in about 40% in the bladder, as well as elsewhere.

Unfortunately, some patients are very sensitive to the fillers used to make up Atarax. So, you have four options:

1. Try Atarax or the Vistaril brand name. Unfortunately, Pfizer has stopped making Atarax pills through December 2003.
2. Try the different generics to see if it will bother you, but try them in small amounts.
3. You could also try the hydroxyzine elixir, which has a very small amount of alcohol in it but at least, there, you can take one teaspoon (5mg) while the smallest pill is 25 milligrams... and it doesn't have the fillers that irritate others.
4. The final approach to ask your pharmacy to take pure hydroxyzine powder and just put it into a little capsule in which case there will be no filler at all. A number of patients that have other problems have resorted, effectively, to that! You just have to have a pharmacist to help you!

#12 Bonus Question - A recent urodynamic study showed that my bladder does not function. I use my abdominal muscles to urinate. Does this indicate a malfunction of the bladder or of the pudendal nerve that serves it?

 Dr.. Theoharides -  It could be either one or a local "muscural dystrophy" of sorts; you really need a neuro-urologist and specialized tests to sort out this problem

#13 Bonus Question - How does Hypothyroid Neuropathy affect the nerves to the bladder and what will make nerves heal?

Dr. Theoharides - This term is more descriptive than accurate. In hypothyroidism, the nervous system tends to be "sluggish" in many organs, but it usually corrects itself whn the thyroid problem is taken care of.

#14 Bonus Question - Is diet a factor for neuropathic pain? What else is there when neither neurontin nor elavil help?

Dr. Theoharides - The drugs mentioned below will probably be the way to go in the near future

• Giannantoni A, Di Stasi SM, Stephen RL, Navarra P, Scivoletto G, Mearini E, Porena M. Intravesical capsaicin versus resiniferatoxin in patients with detrusor hyperreflexia: a prospective randomized study. J Urol 167:1710-4, 2002.