Date: August 17, 1999
Interstitial Cystitis Network - Chat Log (© 1999, www.ic-network.com)
Topic: A glimpse at Quercetin, a promising treatment for prostatitis
Speaker: Dan Shoskes, MD, University of California, Los Angeles USA
<icnmgrjill> Welcome everyone to the ICN support chat for August 17, 1999. Just a moment ago we had an earthquake here in Northern California, which is a very unsettling way to begin a meeting. However, I think we can continue. I'd like to welcome Dr. Dan Shoskes this evening. Dr. Shoskes is one of the most active urology physicians on the internet, which makes it a double pleasure for us because we can discuss and some of the other medical issues we currently see online. But, for tonight, our topic Quercetin. Dr. Shoskes is an Associate Professor of Urology at UCLA Medical School. He is also the Surgical Director of Renal Transplantation and Director of Prostatitis Clinics at Harbor-UCLA and the Institute for Male Urology. He has two web sites which you can review: http://www.dshoskes.com/ & http://www.urol.com. Welcome Dr. Shoskes!
<dshoskes> Thank you very much. It's great to be here in calm SOUTHERN CA.
<icnmgrjill> We have a presentation tonight, so let's go ahead and get that started and then we'll take Q&A from the floor. If you have a question for our speaker, please whisper it to diane, julie or myself and we will make sure that you get placed into the queue.
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Hello, it is a pleasure to join you tonight. I need to stress off the bat that most of my clinical and research activities have not focussed on interstitial cystitis, but rather on renal transplant injury and chronic prostatitis. Nevertheless, I believe that there may be common themes in these inflammatory disorders, which may be treatable with similar compounds. I would like to start with an introduction to my thoughts on IC. I won't burden you with the reference list, but will make it available for the final transcript.
Several etiologies have been proposed to explain the development of IC including infectious, autoimmune, inflammatory (mast cell mediated), neuropathic, traumatic and dietary. An infectious etiology is supported by the epidemiology of the disorder, affecting primarily young sexually active women who are also most prone to bacterial cystitis. Specific bacterial species, not present in normal controls, have been found in IC patients by fastidious culture techniques (1) and by identification of 16 S rRNA bacterial sequences (2) . Nevertheless, not all studies have isolated these bacteria in IC patients (3). Antibiotic therapy is seldom effective and this may be due to the anti-inflammatory rather than the anti-infective properties of these agents. Light and electron microscopic tissue examination typically fail to identify micro-organisms in IC patients (4). Thus a infectious etiology for IC is not fully supported.
An inflammatory response in the absence of infection can be the hallmark or an autoimmune disorder. Support for an autoimmune mechanism for IC comes from the demonstration of increased HLA expression in the bladder wall(5), presence of auto-antibodies in patients with IC and the favorable clinical response (in a small study) to the immunosuppressive cyclosporine(6, 7). However, the autoimmune theory is disputed by a lack of either a change in T cell populations (8), or T cell activation markers in these patients (9).
An inflammatory etiology distinct from classical autoimmunity has long been suspected in IC. Clinical support is seen in the classical cystoscopic features of the disorder, especially ulceration and glomerulations. While several leukocyte lineages have been identified in the urine of IC patients (10), the presence of mast cells in the bladder muscle has long been suspected as a marker and etiologic agent for this disease. Several studies have demonstrated mast cells in the muscularis and submucosa of bladder biopsies in patients with non-ulcerative IC (11), with evidence for mast cell activation (12). Nevertheless, many patients with clinical criteria for IC often do not have bladder mastocytosis(13). Thus it is often difficult to distinguish IC from other bladder disorders solely on mast cell counts (14).
Another suggested mechanism for IC is the loss of the glycosaminoglycan layer of the urothelium (15) which could lead to exposure of deeper bladder layers to toxins in the urine resulting in inflammation. This theory is supported by the presence of hyaluronic acid in the urine of IC patients (16). Furthermore, pentosan polysulphate therapy which can replenish the urothelium produced a positive clinical response in a subset of IC patients (17). Intravesical therapy with hyaluronic acid also produced a positive response(18). Not all studies support a loss of the glycosaminoglycan layer(19) and the etiologic value of this finding has been questioned(20).
A neuropathic inflammatory etiology for IC has also been suggested based on an increase in substance P in nerve fibers (21), increased nerve growth factor levels (22) and histologic evidence of neural inflammation 20) in IC patients. While direct interventions to intervene with this mechanism are lacking, some support is found in the symptomatic response to tricyclic antidepressants and neuropathic agents such as gabapentin.
Clearly then, there are competing theories as to the mechanism and pathophysiology of IC, each with at least partially conflicting evidence and without a unifying theme. We have been interested in the analysis of chronic proliferative and inflammatory disorders, and in particular novel compounds that may be used to treat them.
Bioflavonoids are polyphenolic compounds found in plants, especially onions, spices, green tea, and red wine. They have anti-oxidant properties, both as free radical scavengers and as inhibitors of xanthine oxidase. In addition, they have anti-inflammatory properties, blocking both chemokines and cytokines and they interfere with tyrosine kinase enzyme activation, inhibiting the division and growth of T cells. Some bioflavonoids have been shown to decrease nitric oxide production through inhibition of the inducible NOS gene. Finally, they have antimicrobial and anti-fungal properties. We have focussed our research interest on the bioflavonoid quercetin.
In a recent study of ours in men with nonbacterial prostatitis, 67% of patients taking a purified quercetin 500 mg capsule twice a day had a significant improvement in symptoms (at least 25% improvement in symptom score) versus 20% of the men taking placebo. Using a quercetin formulation that includes bromelain and papain to enhance quercetin absorption (Prosta-Q: http://www.prostaq.com) 82% of the men had a significant improvement in symptoms.
In an unblinded open label study done by a colleague of mine in Canada, 51% of his IC patients noted improvement on quercetin. I should emphasize that a standardized formulation was not used in this preliminary study.
Why might quercetin help in IC? It may be due to a reduction in inflammation through the ability to block chemokines (molecules that enable white cells to "stick" to tissues) or cytokines. It may be through inhibition of cell growth signals such as tyrosine kinase that prevent excessive cell proliferation within ulcers or glomerulations. It may be through direct neural effects, since some bioflavonoids have be shown to have similar properties to tricyclic anti-depressant drugs (such as Elavil).
How could L-arginine which increases nitric oxide (NO) production and quercetin which inhibits NO production both be beneficial for IC patients (a question that has been asked on the newsgroup)? It is very important to remember that NO is a ubiquitous molecule with varied local and systemic functions that interacts with 1000's of other molecules. The state of knowledge of the relationship between NO and IC is very preliminary. It is very plausible that the actual benefit of L-arginine is not related to changes in NO per se, but to alterations in expression of other molecules that NO interacts with. For instance, we know that NO can stimulate expression of the inducible hemoxygenase gene (HO-1), which we have also shown to be stimulated by quercetin. I think that the first question of both l-arginine and quercetin is whether they are truly effective in patients with IC. If they are, the scientific question of mechanism can be addressed.
We are interested in studying quercetin in IC patients, both for its effects on symptoms and on urinary parameters of oxidant stress and gene expression. Farr laboratories, who made the Prosta-Q for us (which also contains Saw Palmetto and Zinc for prostatitis) will make a quercetin/bromelain/papain combination specifically for use in the study which will be performed (ironically enough) at the Institute for Male Urology (http://www.urol.com).
REFERENCES:
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::::::::::::Q&A Begins:::::::::::::
<icnmgrjill> Thank you Dr. Shoskes. Folks, I do have an earthquake update. It was a 5.0, with an epicenter about twenty miles north of San Francisco. Okay... let's take some questions.
<icnmgrjill> Dr. Shoskes.. one of the things that we find so interesting in this relates to nitric oxide and l-arginine and how the research continues to contradict itself. On one hand, we know that nitric oxide aids in urination. On the other hand, higher levels of nitric oxide can be damaging. Can you clarify this for us?
<dshoskes> It's important to remember that NO is really found all over the body in nerves, muscles and cells and has many functions depending on the local environment. It can be difficult to relate an isolated finding such as decreased NO activity in the urine of patients with IC and immediately conclude that giving a substance which stimulates NO production (like L-arginine) will automatically help.
<dshoskes> As I said the presentation, I think it is important first to see what gives symptom relief clinically and then sort out the mechanisms later.
<icnmgrjill> Some researchers have come up publically with the belief that prostatitis is, in fact, misdiagnosed IC patients. Do you agree with this?
<dshoskes> As both diagnoses can sometimes be diagnoses of exclusion based mostly on symptoms of the patients, it is not surprising that some have this view since there is considerable overlap in the symptoms. I have had men diagnosed with prostatitis undergo bladder distension with cystoscopic features of IC, but as I am sure your audience knows these findings have also been found in asymptomatic women. Unfortunately, the standard therapies for IC have not been particularly effective in these men (eg DMSO, elmiron). We will hopefully be involved with a study of higher dose Elmiron in men with prostatitis symptoms next year. Quercetin may help a proportion of patients with both disorders if in fact the etiology is the same or similar.
<icnmgrjill> Would it be fair to compare prostatitis with female urethral syndrome or just a urethral syndrome?
<dshoskes> The spectrum of symptoms in men with CP may focus on penile/urethral pain exclusively, or may be associated with the full spectrum of voiding dysfunction seen in women with IC (although the truly debillitating frequency seems less common)
<icnmgrjill> Perhaps we should clarify what prostatitis is?
<dshoskes> The type of prostatitis we are referring to that has been compared with IC is nonbacterial prostatitis or prostatodynia. In these patients, culture of urine and prostatic fluid is negative for bacteria but inflammation may be seen. The symptoms are pain, voiding dysfunction and sexual dysfunction. The true etiology is as controversial as that for IC, with infectious, autoimmune, inflammatory, neuromuscular and psychiatric etiologies all having their proponents.
<icnmgrjill> And.. in terms of age levels.. what are the ages of the men that you are seeing? There's is a perception that bladder/pelvic/prostate dysfunctions are a function of aging, yet we clearly see many young men and women with bladder and prostate issues.
<dshoskes> The age range of my patients is 18 to 80 with a median of 43 years. Patients I see have a median duration of 4 years of symptoms and have seen a median of 4 Urologists before me. It clearly can be a disease of younger men with normal sized prostates <over>
<icnmgrjill> Have you found any evidence of couples (husbands and wives) passing between each other any type of inflammation during sex?
<dshoskes> This is a complex question, because urinary tract infections can be caused in women after intercourse because of mechanical means rather than an infection in the semen. I believe that known STD's that have been implicated in prostatitis can clearly be passed, such as chlamydia or mycoplasma. However, in the typical patients we see with positive cultures for common skin and vaginal organisms, I doubt that they are causing the symptoms in the women or that there is a "ping pong" effect for the man. The test that I suggest to patients who are concerned about this is to use a condom for a period of time. In most couples who have tried this, the condom did not make a difference, but my experience with this is small.
<icnmgrjill>Actually, this just came up yesterday in one of our message boards. Have you seen any correlation or relationship to latex allergies (as used in condoms) as a causative factor for either men or women?
<dshoskes> That is a very interesting question. I have not seen this in my practice, although it is a theoretical possibility. I would expect men with this problem to either have a local skin rash or nasty systemic symptoms if they had such an allergy, and that has not been the case in any of my patients.
<icnmgrjill>Our next question is about the symptom of pain that men and women experience that is, at times, painfully arousing. We've certainly seen this in women who struggle to find to reduce clitoral pain and inflammation. We know that many of our men have reported pain, particularly at the tip of their penis. Do you have any suggestions on how to reduce this very unpleasant sensation?
<dshoskes> In my prostatitis patients, they seldom report sexual stimulation but do often have prolonged painful erections that are not associated with sexual stimulation. First, penile pain can be referred pain from bladder spasm, so that can sometimes be helped with anti-cholinergics (eg Detrol, Ditropan). If the pain or stimulation is neuromuscular in origin, we have had some success with Elavil and/or Neurontin (gabapentin).
<icnmgrjill> One of our IC men struggles with the process of catheterization. He was excited to hear about Quercetin (or basically any non invasive treatment ) so that he could avoid the use of a catheter. Do you have any suggestions on how to make that process easier or less painful for men with IC or prostatitis?
<dshoskes> Well, catheterization in men does present some challenges that we don't face with women (eg length of urethra and presence of prostate which itself may be painful) The best recommendation is to use a viscous lidocaine jelly that comes in a "squirt" applicator and instill in the urethra. Then hold the tip of the penis to prevent it from leaking out for at least 20 minutes. Since the female urethra is so short, some dip a cotton tip applicator in the viscous lidocaine and insert just the tip into the urethra, again for at least 10-20 minutes. Quercetin is an oral capsule, so obviously catheterization is not an issue. We have not tried it as a local therapy as of yet.
<icnmgrjill> Carol wants to know if you had a suggestion on the amount of neurontin that could be taken to help reduce clitoral pain?
<dshoskes> Neurontin can be very tricky to prescribe and should only be used by physicians who are aware of the dose ranges, interactions and side effects. That said, we have used anywhere from 300 mg once a day to 900 mg three times a day. Pts have very individualized responses and some are even knocked out by the 300 mg once a day dose.
<icnmgrjill> Do you have any comments about fastidious bacteria perhaps being the cause of IC and prostatitis. As we all know, the work of Dr. Fuggazzotto and others in the IC community has contributed some evidence of a bacterial element. Over in the prostate community, the work of Feliciano in the Phillipines is often discussed. Any further comments?
<dshoskes> I mentioned the conflicting data on 16 S ribosomal data in IC in my initial presentation. The problem with finding bacteria in any body fluid or tissue is differentiated between colonization and infection. By definition, to have infection there must be local tissue injury and a reactive inflammatory response to that injury. Therefore, finding bacteria in patients alone is not necessarily proof of infection. I do believe that prostatitis can be caused by "nontraditional" pathogens, especially Gram positive organisms. We recently published a paper where we discovered a new bacteria found only in prostatitis patients and not controls, but have not yet proven what is cause and effect: 1. Tanner M. A., Shoskes D., Shahed A., Pace N. R. : Prevalence of Corynebacterial 16S rRNA Sequences in Patients with Bacterial and "Nonbacterial" Prostatitis. J Clin Microbiol, 37: 1863-1870, 1999.
<icnmgrjill> And so the next logical question involves, of course, the use of antibiotics as a prophylactic treatment for prostatitis or IC. Any comments?
<dshoskes> I can't comment on antibiotic therapy in IC because I simply don't have sufficient experience. In our patients with chronic prostatitis, most have failed multiple courses of antibiotics, although we have been able to get a durable relief of symptoms with antibiotics +/- prostatic massage or alpha blockers in over 1/3 of these patients: 1. Shoskes D. A., Zeitlin S. I. : Use of prostatic massage in combination with antibiotics in the treatment of chronic prostatitis. Prostate Cancer and Prostate Diseases, (in press): 1999.
<icnmgrjill> Are you aware of any physicians in the US or any other country exploring Quercetin as a treatment for IC??
<dshoskes> I have collaborated with Dr. Blair Egerdie in Kitchener, Ont Canada in our preliminary studies. As far as I know, we are the only ones studying this compound, but of course since the info is freely available on the net, it would not surprise me if others are trying it
<icnmgrjill> This gives us the opportunity to discuss product quality. I know that some might be tempted to run to any health food store and try a supplement that might contain Quercetin and obviously this has risks. Would you give us your wisdom on consumer safety and awareness with alternative strategies?
<dshoskes> Thanks to our 1994 congress, there is no FDA oversight on quality in the supplement industry. Therefore there is no guarantee that supplements contain what they say. I saw a study from 2 yrs ago, a watchdog group bought Saw Palmetto all over the country and found that only 30% actually had the SP that they claimed it had. In our studies, we were able to use a purified form of quercetin to ensure absorption. We now use Prosta-Q, which Farr labs made for us with a guarantee of purity. As I said, they will also make us a version for IC. That is not to say that all other forms are bad, but unfortunately, you just don't have any legal guarantees.
<icnmgrjill> Any side effects with Quercetin?
<dshoskes> The most common side effects we have seen have been mild nausea if taken on an empty stomach (we always suggest taking it with meals). A few patients have had mild headaches with high doses. So far all side effects have subsided when the quercetin was discontinued.
<icnmgrjill> Do prostatitis patients experience related conditions, such as IBS or allergies?
<dshoskes> There is a high incidence of psychological problems, which of course could be cause or effect. The current multi-center NIH prostatitis study of which we are a participating center is trying to answer this question prospectively. I have seen patients with irritable bowel, sinusitis and joint problems, but without large numbers it is hard to prove a statistical correlation.
<icnmgrjill> Our last guest speaker was Dr. Jerome Weiss, who talked in depth about the role of pelvic floor dysfunction (i.e. the development of weakened muscles and trigger points) as a possible causative factor. Obviously, pelvic floor therapy is easier for women than men. Is it worth exploration for men with prostatitis?
<dshoskes> I believe that patients with negative cultures and no evidence of inflammation likely have symptoms caused by pelvic floor myalgia. In these patients we have used physical therapy and muscle relaxants. Probably a subset of men who improve with prostatic massage get relief not from any prostate effects but rather from massage of the nearby pelvic muscles (research currently underway by Dr. Anderson at Stanford).
<icnmgrjill> One of the growing areas of discussion is the use of a nerve stimulator (i.e. Medtronics Interstim) as an option for patients who do not respond to other therapies. Is this considered an option for prostatitis patients and do you have any comments about that particular treatment approach?
<dshoskes> Dr. Stuart Chalfin, in my area, has extensive experience with this and I have referred him a few patients, but I can't report on the results yet. I suspect that male patients with significant urinary symptoms as well as pain are better candidates than those with pain alone. The nice therapy is that a temporary stimulator can be used to check whether it actually helps before more permanent surgery is performed.
<icnmgrjill>Would you share with us any information for male patients who would like to participate in the prostatitis study?
<dshoskes> Criteria for inclusion are chronic pelvic pain for at least 6 months. Men have to be off of all antibiotics for at least 3 months and cannot have had previous prostatic surgery. The prostatitis foundation web page, an excellent patient resourse (http://www.prostate.org) has a page devoted to the study.
<icnmgrjill> Thank you for speaking with us tonight Dr. Shoskes. We do appreciate the gift of your time.
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