Excerpted from the April 21, 2003 ICN Guest Lecture
Lecturer: Dr. Theoharis Theoharides
Professor of Pharmacology & Internal Medicine
Tufts University, Boston MA.

In this issue:

1. What do you think of pudendal neuralgia
2. If, as a mother with IC, if her daughter will also develop IC?
3. 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??
4. How does DMSO works.. especially if it burns us?
5. Could having repeated UTI's contribute to developing IC?
6. Educational CD about IC & Algonot?
7. Is IC and prostatitis are pathophysiologically identical, since it also appears that they have identical symptoms?
8. Does IC have a connection with Reflex Sympathetic Dystrophy?
9. Do you have any thoughts about Aloe Vera and IC?
10. Can constant pus in their para-urethal glands along the urethra contribute to some neuroinflammation??
11. 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?
12. 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?
13. How does Hypothyroid Neuropathy affect the nerves to the bladder and what will make nerves heal?
14. Is diet a factor for neuropathic pain? What else is there when neither neurontin nor elavil help?
15. Can having surgery bring about IC?

Disclaimer - Please remember that no speaker, physician or medical care provider can give personal medical advice via the web. Always review any information that you receive on-line with your personal medical care provider. Only your personal doctor can and should make medical recommendations to you

------------------- 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.