key points on male sling

read below from literature; we know erosion will be a delayed problem.

tsk tsk tsk


Even though there was no erosion in the first series of male slings that were presented, we know from previous experience with female population that the use of synthetic material under the urethra bears a risk of erosion of adjacent tissues. Such complication, quite frequent with the use of some substances that were employed in the past for treating female SUI, has turned the autologous fascia into the standard material for treatment of SUI in incontinent women.
The use of orthopedic anchors placed in the ischiopubic rami allows the proper fixation of the fascial flap to the bony tissue in a safe and technically simple way. The option for the use of anchors is based in the easy handling, low cost, safety and comfort since the suture thread is already present in the material. The cost of these anchors is less than 5% of the artificial sphincter's value, making the procedure widely advantageous even when using 4 units for proper fixation.

male sling article

European Urology - Efficacy of the InVance™ Male Sling in Men with Stress Urinary Incontinence

Wednesday, 21 February 2007

Volume 51, Issue 2, Pages 498-503 (February 2007) 1. Introduction: Male stress urinary incontinence is the result of de novo sphincter insufficiency and is a potential complication of prostate surgery. It is particularly common after radical prostatectomy, but can also occur after surgical adenomectomy or endoscopic resection of the prostate. Regardless of the severity of the incontinence observed in the postoperative period, the condition often improves during the subsequent period of months. In addition, recovery can be accelerated by means of bladder training/sphincter reeducation. A minimum delay of 6 mo to 1 yr is needed before envisaging an active treatment for any incontinence resulting from surgery that the patient feels is a handicap. The artificial sphincter is currently preferred treatment in this patient group [1], [2]. The technique involved has been largely standardized, but is complex and not without risk [3]. Although excellent results are obtained in terms of quality of life, there is still a degree of residual incontinence [4]. Currently, periurethral injections, whose action is often incomplete and transitory, tend to be used less frequently. New techniques such as periurethral balloons [5] and bulbourethral slings [6], [7] have also been developed in recent years and have shown encouraging results. The concept of bulbourethral compression as a treatment for male stress urinary incontinence was first introduced by Berry [8] and developed by Kaufman [9]. The technique consisted of compressing the bulbar urethra by means of a silicone pad attached to the corpus cavernosum by several strips. The poor results obtained and a high level of complication resulted in abandonment of this procedure [10]. The success first of bladder neck suspension techniques using the vaginal approach [11], [12] and then of urethral support by means of a synthetic sling in women [13] breathed new life into the concept of urethral compression in men as a means of treating stress urinary incontinence after prostate surgery. The first publications [14], [15], [22] reported encouraging results. From a technical point of view, two approaches were described. The first consisted of making a urethral support using one or more suspended slings with a retropubic approach and, the second, using a purely perineal approach, of performing bulbourethral compression by means of a sling attached to the pubic bone. The InVance™ bulbourethral sling is made of synthetic mesh and exerts pressure on the urethra, reducing the possibility of urinary leakage. We previously described our preliminary results using this procedure [16]. Hence, we report a series of 50 patients with stress urinary incontinence treated consecutively with the InVance™ bulbourethral sling with regards to short-term follow-up. 2. Patients and methods 2.1. Patients Between June 2003 and April 2005 the InVance™ sling was implanted into 50 patients with stress urinary incontinence. The incontinence was the result of prostate surgery in 49 patients (33 radical prostatectomies, 13 combined endoscopic prostate resection and focalized ultrasounds for cancer, and 4 endourethral prostate resections for benign prostatic hyperplasia) and sphincter insufficiency after pelvic trauma in 1 patient. Eight patients had a past history of radiotherapy. The incontinence was quantified arbitrarily by the number of pads used per day. It was considered to be mild (grade 1: one to 2 pads) in 10 cases, moderate (grade 2: three to four pads) in 30 cases, and severe (grade 3: three to 5 or more pads or use of a penile sheath) in 10 cases. A full preoperative workup was conducted including debimetry, postvoid residual (PVR) urine measurement, and vesicourethral fibroscopy; urodynamic evaluation was performed on 26 patients. All patients had previously undergone pelvic floor exercises. Twelve patients had been unsuccessfully treated with trans-sphincter macroplastic injections, and one patient had undergone an explantation of an AMS 800 artificial urinary sphincter because of urethral erosion. 2.2. Methods The procedure was performed with the patient in the dorsal lithotomy position, and with a 16 or 18 Charrière urinary catheter in place under general or spinal anaesthetic. Preventive antibiotic treatment by a loading dose of Cefacidal was administered. The surgical approach used was perineal, with a 5-cm vertical incision made between the scrotum and the anus. Once through the subcutaneous plane and after incision of the Colles fascia, the bulbocavernous muscle was exposed. The dissection was then made laterally in the direction of the right and left ischiopubic branches. The bony relief was uncovered by incising the periosteum from the pubic symphysis to be sure that the screws could be directly and solidly inserted into the bone. Care was taken not to damage the corpus cavernosum during the dissection. The first screw, attached to a Prolene no. 1 thread, was put in place by means of the InVance™ electric screwdriver at the upper end of the ischiopubic branch, 0.5cm under the symphysis. A second screw was placed 4cm lower, and the third between the first two; both had Prolene no. 1 threads attached to them. The rectangular sling used was made of multiperforated polyester coated with silicone and measured 7cm long×4cm wide. The polypropylene threads were cut at the end and passed through the mesh of the sling along the length of its right edge. The sling was then attached to the right ischiopubic branch by knotting the three threads, then tensed to a maximum towards the opposite ischiopubic branch. The left-hand threads were passed through the plate, taking the obliqueness of the ischiopubic branch into account, and then knotted. In its final position, the sling compressed the urethra along a 4-cm length. A cough test was performed systematically in patients undergoing the procedure under spinal anaesthesia. The procedure ended with closure of the wound in two planes without drainage. The urinary catheter was removed on the first or second postoperative day. If there were no complications, the patient was able to leave hospital 24h after removal of the urinary catheter, provided that urination without significant residue (<100ml) had been restored. Follow-up controls were routinely scheduled at 1, 3, and 6 mo postoperatively and every 6 mo thereafter. The efficacy of the sling procedure was assessed in all patients by medical interview. The degree of urinary incontinence was quantified by the number of pads used per 24 day. De novo urinary disorders were sought during the interview and their intensity evaluated by means of the International Prostate Symptom Score (IPSS), debimetry, and measurement of PVR urine. Patient satisfaction was evaluated by means of a simple verbal scale. The treatment was defined as having been a success if the patient no longer used any form of protection (patient cured) or one protection per day (patient improved), without de novo urinary disorders and without significant PVR urine (<100ml). In addition, the patient had to feel satisfied with the result. In all other situations, the treatment was considered to be a failure. 2.3. Statistical analysis The actuarial success rates were calculated with the use of the Kaplan-Meier method and compared with the use of the log-rank test. 3. Results The mean age of the patients was 70 yr (48–81). Median follow-up was 6 mo (1–22) (Table 1). Twenty-five (50%) patients were dry, 13 (26%) patients had improved but still needed to wear one pad per day, and 12 (24%) patients had not obtained any improvement. Of the eight patients who had previously undergone radiotherapy, two (25%) were dry, and the other six (75%) were incontinent. Among the 22 patients with a minimal follow-up of 1 yr, 14 were considered as dry or improved (success rate=63.6%). Among the 28 patients with follow-up of less than 1 yr, 24 patients were considered dry or improved (success rate=85.7%). In our series, no patient has reached a 2-yr follow-up yet. Failure was generally observed immediately after removal of the urinary catheter and postoperatively in the first 6 mo. After this period, all the patients who were dry or who had improved remained stable, regardless of the length of the postoperative period (Fig. 1). One patient underwent a second procedure, giving an overall number of implants of 51. Table 1. Continence at 1-, 3-, 6-, 12- and 18-mo evaluation Follow–up visits 1 mo 3 mo 6 mo 12 mo 18 mo No. of patients (N) 50 29 17 14 6 Dry or improved (n [%]) 42 (84) 26 (89.6) 16 (94.1) 14 (100) 6 (100) Failed (n [%]) 8 (16) 3 (10.4) 1 (5.9) 0 (0) 0 (0) Fig. 1. Kaplan-Meier curve of success rates (cured or improved) in 50 patients who underwent the InVance™ male sling procedure for urinary incontinence. IPSS score and urodynamic results are summarized in Table 2. All patients who were dry or improved were satisfied with the outcome and did not present any obstructive or irritative de novo urinary disorder. This finding represented a global success rate of 74.5% for the 51 procedures conducted. The success rate in the patients with mild or moderate incontinence was, respectively, 90% and 76.6% versus 50% in the patients with severe incontinence (Fig. 2). In addition, the failure rate in the patients with a past history of radiotherapy was higher: 75% versus 16.3 % in the nonirradiated patients (Fig. 3). Table 2. Symptomatic and urodynamic outcome variables Follow–up visits 1 mo 3 mo 6 mo 12 mo 18 mo Mean IPSS (range) Not available 8.6 (5–18) 9.1 (5–16) 8.8 (6–14) 8 (4–16) Mean Qmax (range) 16 (9–32) 16.2 (10–47) 18.5 (9–56) 18.9 (9–45) 17 (10–37) Mean PVR (ml/s) (range) 55 (0–145) 38 (0–150) 42 (0–200) 28 (0–75) 24 (0–105) IPSS: International Prostate Symptom Score; Qmax: maximum urinary flow rate; PVR: postvoid residual. Fig. 2. Kaplan-Meier curve of success rates (cured or improved) after the InVance™ male sling procedure, according to the degree of preoperative incontinence. Fig. 3. Kaplan-Meier curve of success rates (cured or improved) after the InVance™ male sling procedure, according to past history of radiotherapy. Most patients reported postoperative perineal pain, which diminished in the course of the first postoperative month. In six (12%) patients, perineal pain of an intensity of more than 3 on an analogue visual scale (AVS) persisted for more than 3 mo postoperatively and required analgesic management. In one (2%) patient, perineal pain of an intensity varying between 3 and 5 on an AVS was reported. Other morbidities reported included two cases of spontaneously resolving perineal haematoma and acute urine retention on removal of the urinary catheter in six (12%) patients. This urine retention was transitory and in all cases resolved after 48 to 72h of catheterization. No cases of chronic urine retention were recorded. An infection of the sling occurred within the first postoperative month in two patients and at 3 mo in one patient who was also receiving immunosuppressants. The infection required explantation of the sling in all cases. Exacerbation of irritative urinary symptoms occurred in one patient leading to removal of the prosthesis. No cases of pubic osteitis or urethral erosion have been reported to date. In one patient, the implantation of an artificial urinary sphincter was performed at the same time as explantation of the InVance™ because of irritative urinary symptoms. In another patient, the implantation of an artificial urinary sphincter was performed successfully 8 mo after the removal of an InVance™ sling because of infection. A third patient benefitted from the implantation of a second InVance™ sling 12 mo after the explantation of the first sling because of infection. 4. Discussion Comiter [17] described a technique for the compression of the bulbar urethra using a polypropylene bulbourethral sling attached to the ischiopubic branches with four titanium screws. The originality of the compression exerted by the sling was that it was not circumferential and that it was not in direct contact with the urethra. The sling was applied against the preurethral fat with neither incision in the bulbocavernous muscle nor dissection of the urethra. This technique, using a purely perineal approach, made it possible to guarantee immediate continence as soon as the urinary catheter was removed, as well as spontaneous urination without manipulation. With an average follow-up of 12 mo, Comiter reported a success rate of 76%. The technique has since been applied by other teams with success rates varying between 55% and 76% [18], [19], [20]. To date, we have used this procedure on 49 patients with urinary incontinence after prostate surgery and 1 patient with urinary incontinence after pelvic trauma. With a global success rate of 74.5%, the results are comparable to those published recently [18], [19]. In the current study, outcome was better in patients with mild or moderate incontinence (90% and 76.6%, respectively). Moreover, 50% of patients were dry. A careful selection of patients and maximum sling tension may explain this rate of dryness. The failures, most often in cases of severe incontinence (50%) or a past history of radiotherapy (75%), were observed in the immediate postoperative period on removal of the urinary catheter or within 1 to 3 mo. These results imply that the more severe the incontinence is, the less efficacious the treatment is. Overall, both high-grade incontinence and prior radiotherapy are bad prognostic criterions. These results follow a similar pattern as those achieved by Rajpurkar et al. [19] who reported success rates of 83% and 50% in cases of mild or severe incontinence, respectively, and by Castle et al. [18] with rates of 13% and 47% in irradiated and nonirradiated patients, respectively. To be fully effective, the sling must be tightened as much as possible to ensure sufficient occlusion of the bulbar urethra. Its very mode of action, however, probably renders it less effective than the artificial sphincter and may explain the failure rate in patients with severe incontinence. The higher failure rate in patients who had undergone radiotherapy may be due to increased periurethral fibrosis, thus making the compression less effective. No cases of erosion were recorded in the current series, but it cannot be ruled out that progressive atrophy of the preurethral tissues caused by the permanent compression exerted by the sling could reduce its efficacy and, in the long term, lead to poorer results [18]. Most authors perform a perioperative sphincterometry to adjust the sling using the retrograde leak point pressure (RLPP) [21]. The aim is to tighten the sling to obtain a pressure of between 50 and 70cm H2O, corresponding to the pressure exerted on the urinary sphincter [17], [21]. The aims of this adjustment are first to avoid the excessive compression of the perineal neurovascular structures, which are the source of pain [6], and second to reduce the risk of urethral atrophy [17]. It must nevertheless be noted that, despite the considerable tension exerted on the sling, the perineal pain observed in the current series in the postoperative period eased spontaneously in most cases within 1–3 mo, and only one patient continued to suffer from chronic sequelar perineal pain. The permanent action of the sling on the bulbar urethra raises the question of urinary tolerance. Through its obstructive nature, the InVance™ device is effectively liable, in theory, to provoke de novo urinary disorders. One patient did present with aggravated irritative urinary symptoms; he was also incontinent and classified as a failure. The intensity of the urinary symptoms were probably worsened by a past history of radiotherapy. Excluding this patient, no cases of de novo urinary disorders were observed, confirming the high level of urinary tolerance in implanted patients. The episode of urine retention that occurred in six patients on removal of the urinary catheter was, in all cases, transitory and resolved within 48–72h of catheterization. No patients presented with chronic urine retention. These observations corroborate those reported by others [17], [18], [19] and were consolidated by a postoperative urodynamic study that showed an increase in average RLPP without any de novo obstructive or irritative phenomena [23]. The synthetic nature of the device implanted implies a septic risk. In addition there is a potential risk of pubic osteitis, given the fact that the screws are attached to the bone. It is thus essential that all the necessary precautions be taken to avoid contamination of the operating site and the material implanted: sterile urine, perioperative antibiotic therapy, rigorous asepsis, and the shortest possible procedure. Infection rates previously reported are of the order of 2–7% [18], [19], [24] compared with 6% in this series; all of the latter occurred early after implantation and resolved after explantation of the sling and antibiotic therapy. With regards to pubic osteitis no cases were reported in the present study and, in general, the incidence is low. A 1.3% incidence was observed in a large series of 290 consecutive women who underwent bladder neck suspension using suprapubic bone anchors [25]. In two patients in whom the treatment failed, secondary treatment with an artificial sphincter implanted using the perineal approach was beneficial. The polyester sling with its silicone protection is easy to identify and explant because it is not colonized with fibrosis. The screws are left in place. In addition, the incision in the bulbocavernous muscle and dissection of the urethra are made easier by the absence of prior dissection of these tissues during the implantation of the sling. 5. Conclusions The InVance™ bulbourethral sling has been shown to be a simple and effective means of treating mild or moderate stress urinary incontinence in men after prostate surgery. It has the added advantage in men with limited manual dexterity or limited comprehension of spontaneous urination possible without the need for manipulation. Secondary procedures are also feasible in the cases of treatment failure. It is acknowledged that these results are short-term and confirmation of long-term efficacy and safety is required. References 1. Venn SN, Greenwell TJ, Mundy AR. The long-term outcome of artificial urinary sphincters. J Urol. 2000;164:702–706. 2. Gousse AE, Madjar S, Lambert MM, Fischman IJ. Artificial urinary sphincter for post-radical prostatectomy urinary incontinence: long-term subjective results. J Urol. 2001;166:1755–1758. 3. Montague DK, Angermeier KW. Artificial urinary sphincter troubleshooting. Urology. 2001;58:779–782. 4. Dalkin BL, Wessells H, Cui H. A national survey of urinary and health related quality of life outcomes in men with an artificial urinary sphincter for post-radical prostatectomy incontinence. J Urol. 2003;169:237–239. 5. Trigo Rocha F, Gomes CM, Pompeo ACL, Arap S, Lucon AM. A prospective study evaluating the long term efficacy and safety of the adjustable continence therapy (proACT™) for post radical prostatectomy urinary incontinence. Eur Urol Suppl. 2005;4(3):62;(abstract no. 239). 6. Schaeffer AJ, Clemens Q, Ferrari M, Stamey TA. The male bulbourethral sling procedure for post-radical prostatectomy incontinence. J Urol. 1998;159:1510–1515. 7. Madjar S, Raz S, Gousse AE. Fixed and dynamic urethral compression for the treatment of post-prostatectomy urinary incontinence: is history repeating itself. J Urol. 2001;166:411–415. 8. Berry JL. A new procedure for correction of urinary incontinence: a preliminary report. J Urol. 1961;95:661–675. 9. Kaufman JJ. Treatment of post-prostatectomy urinary incontinence using a silicone gel prosthesis. Br J Urol. 1973;45:646–653. . Kaufman JJ, Raz S. Urethral compression procedure for the treatment of male urinary incontinence. J Urol. 1979;121:605–608. 11. Stamey T. Endoscopique suspension of the vesical neck for urinary incontinence in females. Report in 203 consecutive patients. Ann Surg. 1980;192:465–471. 12. Raz S, Sussman EM, Erickson DB, Bregg KJ, Nitti VW. The bladder neck suspension: Results in 206 patients. J Urol. 1992;148:845–850. 13. Ulmsten U, Falconer C, Johnson P, Jomaa M, Lanner L, Nilsson CG, et al.. A multicenter study of tension-free vaginal tape (TVT) for surgical treatment of stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct. 1998;9:210–213. 14. Stamey T. Perineal compression of the corpus spongiosum of the bulbar urethra. An operation for post radical prostatectomy urinary incontinence. J Urol. 1994;151:490A;(abstract no. 1049). 15. Cespedes RD, Jacoby K. Male slings for male urinary incontinence. Tech Urol. 2001;7:176–183. 16. Fassi-Fehri H, Cherasse A, Badet L, Pasticier G, Landry JL, Martin X, et al.. Treatment of post-operative male urinary incontinence by INVANCE® prosthesis: preliminary results. Prog Urol. 2004;14:1171–1176. 17. Comiter CV. The male sling for stress urinary incontinence: a prospective study. J Urol. 2002;167:597–601. 18. Castle EP, Andrews PE, Itano N, Novicki DE, Swanson SK, Ferrigni R. The male sling for post-prostatectomy incontinence: mean followup of 18 months. J Urol. 2005;173:1657–1660. 19. Rajpurkar AD, Onur R, Singla A. Patient satisfaction and clinical efficacy of the new perineal bone-anchored male sling. Eur Urol. 2005;47:237–242. 20. Comiter CV. The male perineal sling: intermediate-term results. Neurourology and urodynamic. 2005;24:648–653. 21. Comiter CV, Sullivan MP, Yalla SV. Retrograde leak point pressure for evaluating post-radical prostatectomy incontinence. Urology. 1997;49:231–236. 22. Madjar S, Jacoby K, Giberti C, et al.. Bone anchored sling for the treatment of post-prostatectomy incontinence. J Urol. 2001;165:72–76. 23. Ullrich NF, Comiter CV. The male sling for stress urinary incontinence: Urodynamic and subjective assessment. J Urol. 2004;172:204–206. 24. Romano SV, Metrebian SE, Vaz F, et al.. An adjustable male sling for treating urinary incontinence after prostatectomy: a phase III multicentre trial. BJU Int. 2006;97:533–539. 25. Goldberg RP, Tchetgen MB, Sand PK, et al.. Incidence of pubic osteomyelitis after bladder neck suspension using bone anchors. Urology. 2004;63:704–708. Hakim Fassi-Fehri, Lionel Badet, Arnaud Cherass, François-Joseph Murat, Marc Colombel, Xavier Martin, Albert Gelet Department of Urology and Transplantation, Edouard Herriot Hospital, Lyon, France Accepted 22 August 2006 published online 7 September 2006. UroToday.com Urologic Trauma & Reconstruction Section UroToday.com Stress Urinary Incontinence Section Reader Comments Please log-in or register in order to submit comments.

my new squidoo site

http://www.squidoo.com/lensmaster/workshop/prostatecancerkills


come visit.
day 6 cayenne pepper.
doing fine.
blood sugar check this weekend.
continuing to adopt china study diet.

peace

day five cayenne pepper trial

As some of you may know, I am taking the cayenne pepper for high blood sugars.
My fastings are 125 right now...now perfect. Will recheck this weekend.
I did up my dose to capsules once a day at meal time...pretty moderate pepper induced indegestion for about ten minutes that does resolve.
yes, stools are a little loose. I am also taking cinnamon. Will keep you posted.

Also, I did tell a good friend and pharma rep about china study today; she has multiple sclerosis. Since I am going to attempt adoption of as much of the diet that I can, I will keep you all informed here...all three of you!

peace

Day 3 of cayenne pepper

okay,

greetings from george rucker
urology and urologist of sarasota and lakewood ranch
george rucker m.d., prostate cancer expert and cayenne pepper expert as it relates to prostate cancer and diabetes.

day 3 of cayenne pepper.
as you all know, i am taking it for glucose intolerance, but at same time, I intend to use myself as teaching example for possible patients taking it to circumnavigate prostate cancer risk.

my blood sugars were looking good today. lower than usual, but one confounding variable is fact that i am exercising more and have given up alcohol for last four weeks. I was drinking a bit too much, so not sure which factor is helping. But, if sugars continue to drop, i will continue to use the pepper.
so far, i took two capsules for first time today. one a day wasnt hurting me yet.

peace

george rucker
urology
urologist

old men's health article where i consulted

At end of article is part about George Rucker Urology.
George Rucker urologist practicing in lakewood ranch and sarasota.
Prostate cancer, interstim, incontinence expert.
Expert in Alternative Urology and Surgery.




Crazy clean freak

Dangerous overgrooming

Kevin Cook Additional reporting by Nicole MaierSeptember 2006
Crazed ear-budding, fierce flossing, wild nasal manoeuvres - here's how the road to hell can be paved with hyperhygieneLike most men, I am a hygiene centrist: I fall somewhere between Queer Eye and Pigpen. Except with ear buds - give me a 300 pack and I'll start twirling till they whir. Yesss! A sucker for that eargasm, I scoffed at the warning on the box: "Do not use swab in ear canal." Who were they kidding?Then came the first ear infection. "You use ear buds, don't you?" the ear doctor asked, poking in my ear canal till it felt like a root canal. Turns out all my swabbing had merely pushed my earwax deeper, where it formed a festering "wax plug". As I winced, the doctor smiled. This man hated ear buds and he was teaching me a lesson. "Never," he said, probing deeper, "put an ear bud down... this... far!"Ow! But I couldn't give it up, so I found a specialist who allows canal cleaning with a swab dipped in hydrogen peroxide. I'm ear-budding again, my eyes rolling up in my head. So the obsession is still there. And so are the risks, as I know all too well. Here's a guide to where hygiene spills across the border into self-destruction.Keep that out of your earSwirling a swab in your ear canal can cause infections and worse. "Push too far and you can rupture your eardrum," says assistant professor of otolaryngology Dr Timothy Hullar. His advice: do nothing. "You don't really need to clean your ears." A few people have trouble with earwax build-up, but they can get by with a few drops of hydrogen peroxide (diluted 50/50 with water) or mineral oil a couple times a week. "Olive oil works, too," Dr Hullar says, "but you may smell like a salad."Limit your nasal manoeuvresDid you know that nose drops and sprays can be addictive? Allergy nurse Bonnie Dooley sees patients who can't go an hour without a spritz of 12-hour nasal spray. Overuse causes "rebound swelling" and ever-worse congestion. Extreme spritzing can also mess with your blood pressure, which means there could be such a thing as killer nose drops.Next time you have a stuffy nose, try plain salt water. Chemists sell squirt bottles of saline solution - cheap. It eases congestion by moistening dry nasal passages and can't be overused. Taking an antihistamine or inhaling steam can also loosen mucus.Cut it out with the clippersCompulsively trimming your toenails can send a nail burrowing back into your flesh. In extreme cases, you can wind up with a bone infection or gangrenous ulcer that may result in amputation. Even ordinary ingrown toenails often require "removing a portion of nail and cauterising the nail root so it will not grow back," says podiatrist Dr Tracey Toback. His advice: "Never wear shoes that are too tight. Always trim toenails straight across. And do not invade the nail bed by trimming too short or too deep into the margins."Lighten up on your teeth"Brushing your teeth does not require a lot of force," says dentist Dr Ronald Goldstein, author of Change Your Smile. Yet he's treated men who've brushed away their enamel (the outer covering of the teeth) and kept going until the gum tissue receded. Continued hard brushing wears away the much softer cementum (covering the root), which may lead to an increased chance of sensitivity, decay and tooth deformity. How can you tell if you're brushing too hard? Check your brush. If the bristles are frayed or splayed after a few months' use, you may be an offender. "If you brush correctly," says Goldstein, "your brush should look pretty much the same after six months as it did when you bought it." And, he adds, "check with your dentist or hygienist to make sure you're brushing the right way for your own mouth".Likewise, flossing is healthy, but not if you garrote your gums. According to Goldstein, "a lot of people saw through their gum tissue", yanking floss back and forth through that tender flesh. Move floss gently under the gums to nab food particles, then up and down each side of the tooth.Hygiene is only skin deepA 2005 survey indicated that 37 percent of men didn't wash their hands after making a deposit at the men's room. Creepy, yes, but then there are those of us who can't stop washing. Some men rub their skin clean off. "They wash and wash an area and then rub it to make sure it's clean," says dermatologist Dr Julian Omidi. "That traumatises the top layer of skin, which then turns thick and brownish. Nerve endings can become further irritated, triggering a vicious circle of itching and rubbing." Even mildly neurotic overwashing strips skin of natural oils and can turn your epidermis into something like pimple-covered bark. This can happen on your face, where too much soap can send oil glands into overdrive, plugging pores and follicles, which triggers acne. Remember, as well, that you could stay perfectly healthy with a weekly bath or shower. When you do scrub up, keep a lid on harsh cleansers. "Try alcohol-free skincare products," says Omidi. "Use a gentle foaming cleanser and don't wash more than twice a day." You don't need to take extreme measures for exfoliation, either: it's a natural. By the time you take your next breath, more than a thousand dead skin cells will have fallen off your body. Exfoliating with abrasive creams or loofahs accelerates the process, but compulsive use can "denude" the epidermis. Don't exfoliate more than two or three times a week.And finally, we reach your dirty bitsWhile a coffee enema might pep a person up, below-the-belt orifices seldom need cleaning. Rectal itching, aka pruritus, can result from poor hygiene, as when faecal particles become stuck in skin folds near the anus. But itching and irritation can also be caused by too much rubbing with toilet paper or too much washing. The rectal area is naturally oily, which prevents irritation. Don't soap away your natural oils. The same goes for your package, which requires a lot less maintenance than you might think. "Scrubbing the pubic area too much can cause ingrown hairs that may turn into pustules," says urologist Dr G Bino Rucker. You should wash carefully but not fiercely. Spare the soap and you won't deplete the oils you need to stave off unsightly events. The best advice: when in doubt, leave your privates in peace.

george rucker urologist pepper again

A curry a day keeps the doctor away?
PA04/07 — January 09 2007
The chemical that gives spicy food its kick could hold the key to the next generation of anti-cancer drugs that will kill tumours with few or no side effects for the patient, say academics at The University of Nottingham.

A study by the scientists, published online in the journal Biochemical and Biophysical Research Communications, has proven for the first time that the chemical compound capsaicin — which is responsible for the burning sensation when we eat chillies — can kill cells by directly targeting their energy source.

It could mean that patients could control or prevent the onset of cancer by eating a diet rich in capsaicin and that existing products to treat conditions such as psoriasis and muscle strain, which contain the compound and are already approved for medical use, could be adapted to tackle this more serious disease.

The Nottingham study has shown that the family of compounds to which capsaicin belongs, vanilloids, can kill cancer by attacking the mitochondria of the tumour cell, commonly known as its 'powerhouse', which produces ATP, the major energy-containing chemical in the body. By binding proteins in the cancer cell mitochondria the compound triggers apoptosis, or natural cell death, without harming the healthy surrounding cells.

Dr Timothy Bates, the study's leader, is a member of the Medical Research Council (MRC) College of Experts and an internationally-renowned researcher in the areas of mitochondrial research and anti-cancer drug development. He said: “This is incredibly exciting and may explain why people living in countries like Mexico and India, who traditionally eat a diet which is very spicy, tend to have lower incidences of many cancers that are prevalent in the western world.”

The compound has been tested in the laboratory on H460 human lung cancer cells, approved by the National Cancer Institute as a member of its 60 cell panel which is the 'gold standard' for testing new anti-cancer drugs, and produced startling results. Dr Bates' research team also tested similar compounds on pancreatic cancer, producing similar cell death to that observed with the lung cancer cells. These results are highly significant, as pancreatic cancer is one of the most difficult cancers to treat and which has a five-year survival rate of less than one per cent.

“As these compounds attack the very heart of the tumour cells, we believe that we have in effect discovered a fundamental 'Achilles heel' for all cancers. The investigation and development of anti-mitochondrial drugs for cancer chemotherapy by our group is unique in the UK and is likely to be extremely significant in man's fight against cancer both here and internationally.”

By its very nature capsaicin, and other vanilloids found in the human diet, are safe because we already eat them in many common foods. And some have already been passed for use in treatments for other medical conditions, reducing the number of hurdles needed to get them approved for use in cancer patients.

Dr Bates added: “To develop a new drug costs pharmaceutical companies in the region of $800 million and takes up to 10 years.

“To develop a drug for a secondary medical purpose costs far less, so compounds such as capsaicin and the others we have identified could mean big business. Capsaicin, for example, is already found in treatments for muscle strain and psoriasis — which raises the question of whether an adapted topical treatment could be used to treat certain types of skin cancer.

“We have already identified a number of compounds that are currently used in man for other diseases that have (secondary) anti-cancer actions. We are currently seeking industrial partners to enable these agents to be used in clinical trials with colleagues from Nottingham and other centres in the UK to treat a variety of cancers both in adults and, in particular, in children's cancers, where their younger cells are already 'primed' to die by apoptosis making them more susceptible to these agents.

“It's also possible that cancer patients or those at risk of developing cancer could be advised to eat a diet which is richer in spicy foods to help treat or prevent the disease.”

The study has brought together researchers from The University of Nottingham's Schools of Community Health Sciences, Medical and Surgical Sciences and Biomedical Sciences and colleagues from the Welsh School of Pharmacy at Cardiff University.

The study is also the first by the newly-established Nottingham UK-China Collaboration on Complementary and Alternative Medicine (NUKCAM), which consists of researchers from The University of Nottingham and the Chinese National Academy of Sciences, including Professor De-An Guo, Head of the Shanghai Research Centre for Traditional Chinese Medicine Modernization. Professor Guo has expertise in separating out chemical compounds in ancient Chinese herbal remedies, and is collaborating with Dr Bates and his colleagues to establish why compounds used in Chinese medicine are successful in treating cancer and a wide range of other diseases.

On a personal note, I have battled high blood sugars as of late. I am going to begin a program of cayenne pepper ingestion combined with cinnamon for my personal blood sugar levels. Also, this will be a nice tolerance test of the pepper regimen to provide guidance for my prostate cancer patients. Wish me luck.

George Rucker, Urologist
M.D. in urology and urologic surgery
Bradenton, Sarasota, Lakewood Ranch, Florida






capsicum pepper
Family: Solanaceae, Capsicum species
Capsicum annuum L.
Capsicum frutescens L.
Source: Simon, J.E., A.F. Chadwick and L.E. Craker. 1984. Herbs: An Indexed Bibliography. 1971-1980. The Scientific Literature on Selected Herbs, and Aromatic and Medicinal Plants of the Temperate Zone. Archon Books, 770 pp., Hamden, CT.
Capsicum pepper refers primarily to Capsicum annuum L. and Capsicum frutescens L., plants used in the manufacture of selected commercial products known for their pungency and color. Capsicum annuum L. is a herbaceous annual that reaches a height of one meter and has glabrous or pubescent lanceolate leaves, white flowers, and fruit that vary in length, color, and pungency depending upon the cultivar. Native to America, this plant is cultivated almost exclusively in Europe and the United States. Capsicum frutcens L. is a short-lived perennial with woody stems that reach a height of two meters, glabrous or pubescent leaves, has two or more greenish-white flowers per node, and extremely pungent fruit. This plant is cultivated in the tropics and warmer regions of the United States.
The reported life zone for capsicum peppers is 7 to 29 degrees centigrade with an annual precipitation of 0.3 to 4.6 meters and a soil pH of 4.3 to 8.7 (4.1-31). Capsicum species are cold sensitive and generally grow best in well-drained, sandy or silt-loam soil. Plantings are established by seeding or transplanting. Flowering usually occurs three months after planting. Hot and dry weather is desirable for fruit ripening. Fruit is generally handpicked as it ripens, and then allowed to dry in the sun, although artifical drying is often employed in Europe and the United States. The fruit may be ground intact or after the removal of seeds, placenta parts, and stalks, increasing the fruit color and lowering the pungency (4.6-66, 4.6-67).
The level of pungency of the Capsicum species depends upon the concentration of capsaicinoids, primarily of capsaicin, in the fruit. Capsicum peppers are classified comnercially by the concentration of capsaicinoids, since confusion about the biological identities of some varieties has made other methods unreliable. Paprika comes from plants with 10 to 30 parts per million capsaicinoids, chili peppers from plants with 30 to 600 parts per million, and red peppers from plants with 600 to 13,000 parts per million (1.5-152). The chemical composition of the Capsicum species includes a fixed oil, pungent principles, volatile oil, and carotenoid, mostly capsanthin, pigments (6.1-65, 2.8-45). An oleoresin is obtained by solvent extraction. Capsicum frutescens L. is much more pungent than Capsicum annuum L.
Capsicum species are used fresh or dried, whole or ground, and alone or in combination with other flavoring agents. Capsicum annuum L. is used in sweet bell peppers, paprika, pimento, and other red pepper products. Capsicum frutescens L. is used in tabasco, tabasco sauce, and other red chili pepper. Fruits of Capsicum annuum L., paprika types, are widely used as coloring agents. The extracts of Capsicum species have been reported to have antioxidant properties (11.1-126). Paprika is derived from Capsicum annuum L. and is used prinarily in the flavoring of garnishes, pickles, meats, barbecue sauces, ketchup, cheese, snack food, dips, chili con came, salads, and sausages (11.1-128). Spanish paprika is called pimento and is generally used for coloring purposes (14.1-10). Chilies and chili pepper from cultivars of Capsicum annuum L. and Capsicum frutescens L. are employed as a flavoring in many foods, such as curry powder and tabasco sauce. Chili powder is a blend of spices that includes ground chilies. Red or hot peppers from Capsicum annuum L. and Capsicum frutescens L. are the most pungent peppers and are used extensively in Mexican and Italian foods. Cayenne pepper is the ground product derived from the smaller, most pungent Capsicum species.
As a medicinal plant, the Capsicum species has been used as a carminative, digestive irritant, stomachic, stimulant, rubefacient, and tonic. The plants have also been used as folk remedies for dropsy, colic, diarrhea, asthma, arthritis, muscle cramps, and toothache. Capsicum frutescens L. has been reported to have hypoglycemic properties (7.1-21). Prolonged contact with the skin may cause dermatitis and blisters, while excessive consumption can cause gastroenteritis and kidney damage (11.1-101). Paprika and cayenne pepper may be cytotoxic to mammalian cells in vitro (7.8-25). Consumption of red pepper may aggravate symptons of duodenal ulcers (7.8-55). High levels of ground hot pepper have induced stomach ulcers and cirrhosis of the liver in laboratory animals (6.1-65). Body temperature, flow of saliva, and gastric juices may be stimulated by capsicum peppers (14.1-35).
Other Capsicum species of some importance include Capsicum chinense, Capsicum pendulum, Capsicum pubescens, and Capsicum minimum. Black and white pepper come from Piper nigrens L., of the Piperaceae family. The name pimento is sometimes used in reference to allspice, Pimento dioica (L.) Merrill, a native of the West Indies and a member of the Myrtaceae family.
Capsicum annuum L. and Capsicum frutescens L. are generally recognized as safe for human consumption as spices/natural flavorings and as plant extracts/oleoresins (21 CFR sections 182.10, [1982]).
[Note: References listed above in parentheses can be found in full in the original reference].

for brainiacs on pepper george rucker urologist

This is an outstanding post for you gearheads brought to you by George Rucker, Urologist in Bradenton Florida.

You can find George Rucker urologist at www.urology-partners.com.
George Rucker, M.D. practices the art of urologic surgery in Sarasota, Bradenton, and Lakewood Ranch. There he is "considered the elite doctor to the stars and the 'doctor's doctor'. As quoted by his famed internal medicine peer Vishal Sharma, M.D.


Inhibition of nuclear transcription factor NF-.kappa.B by caffeic acid phenethyl ester (CAPE), derivatives of CAPE, capsaicin (8-methyl-N-vanillyl-6-nonenamide) and resiniferatoxinUS Patent Issued on November 9, 1999

Inventor(s)
Bharat B. AggarwalDezider Grunberger
Assignee
Research Development Foundation
Application
No. 924365 filed on 1997-09-05
Current US Class
514/532 , Z-C(=O)-O-Y, wherein Z contains a benzene ring 514/557 , Carboxylic acid, percarboxylic acid, or salt thereof (e.g., peracetic acid, etc.) 560/75 Phenolic hydroxy or metallate
Field of Search
514/532 , Z-C(=O)-O-Y, wherein Z contains a benzene ring 514/533 , Compound contains two or more C(=O)O groups indirectly bonded together by only covalent bonds 514/548 , Ring in alcohol moiety 514/557 , Carboxylic acid, percarboxylic acid, or salt thereof (e.g., peracetic acid, etc.) 514/914 , Inflammation 514/921 , SHOCK 560/75 Phenolic hydroxy or metallate
Examiners
Primary: Jean C WitzAssistant: Susan Hanley
Attorney, Agent or Firm
Adler; Benjamin Aaron
US Patent References
5008441Caffeic acid esters and methods of producing and using same Issued on: April 16, 1991 Inventor: Nakanishi, et al. 5021450New class of compounds having a variable spectrum of activities for Issued on: June 4, 1991 Inventor: Blumberg 5591773Inhibition of cataract formation, diseases resulting from oxidative stress, and HIV replication by caffeic acid esters Issued on: January 7, 1997 Inventor: Grunberger, et al.

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Abstract Claims Description Full Text
Abstract
The present invention is drawn to the inhibition of activation of NF-.kappa.B by caffeic acid phenethyl ester (CAPE) and two analogues of CAPE. Tumor necrosis factor (TNF) activation of NF-.kappa.B is completely blocked by CAPE in a dose- and time-dependent manner, as is activation by phorbol ester, ceramide, hydrogen peroxide, and okadaic acid. Additionally, capsaicin (8-methyl-N-vanillyl-6-noneamide) and resiniferatoxin inhibit the activation of NF-.kappa.B induced by different agents.Claims
What is claimed is: 1. A method of inhibiting the activation of nuclear transcription factor NF-.kappa.B in cells in vitro or in vivo, comprising the step of treating said cells with caffeic acid phenethyl ester (CAPE). 2. The method of claim 1, wherein said activation of NF-.kappa.B is induced by an agent selected from the group consisting of tumor necrosis factor, phorbol ester, ceramide, okadaic acid, and hydrogen peroxide. 3. A method of inhibiting the activation of nuclear factor NF-.kappa.B in cells in vitro or in vivo, comprising the step of treating said cells with an agent selected from the group consisting of a 2,5-dihydroxy analogue of CAPE, a 5,6-dihydroxy bicyclic analogue of CAPE, 8-methyl-N-vanillyl-6-nonenamid (capsaicin), and resiniferatoxin. Description
BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates generally to inhibitors of nuclear transcription factor NF-.kappa.B, and the use of these inhibitors in the treatment of pathological conditions in humans. Specifically, the present invention relates to the inhibition of nuclear transcription factor NF-.kappa.B by Caffeic Acid Phenethyl Ester (CAPE); a 5, 6-dihydroxy, bicyclic derivative of CAPE; a 2, 5-dihydroxy derivative of CAPE; capsaicin (8-methyl-N-vanillyl-6-nonenamide); and resiniferatoxin, and methods for using these inhibitors in the treatment of pathological conditions such as toxic shock, acute inflammatory conditions, acute phase response, atherosclerosis and cancer.
Nuclear Factor NF-.kappa.B is a protein specific to B cells and binds to a specific DNA sequence within the immunoglobin light chain .kappa. locus enhancer region. Members of the transcription factor NF-.kappa.B family have been identified in various organisms, ranging from flies to mammals (see Nolan, et al., Curr. Opin. Genet. Dev. 2:211-20(1992); Liou, et al., Curr. Opin. Genet. Dev. 5:477-87(1993); and Baeuerle and Henkel, Annu. Rev. Immunol. 12:141-79(1994)). Members of this transcription factor family are 35 to 61% homologous to each other and have a Rel homology domain of about 300 amino acids. In mammals, the most widely distributed .kappa.B-binding factor is a heterodimer consisting of p50 and p65 (Rel-A) proteins. This transcription factor plays a central role in various responses, leading to host defense through rapid induction of gene expression. In particular, it controls the expression of various inflammatory cytokines, the major histocompatibility complex genes and adhesion molecules involved in tumor metastasis. Dysregulation of NF-.kappa.B and its dependent genes has been associated with various pathological conditions including toxic/septic shock, graft vs. host reaction, acute inflammatory conditions, acute phase response, viral replication, radiation damage, atherosclerosis, and cancer (see Baeuerle and Henkel, Annu. Rev. Immunol. 12:141-79 (1994); and Siebenlist, et al, Annu. Rev. Cell Biol. 10:405-55(1994)). Unlike other transcription factors, the NF-.kappa.B proteins are held in the cytoplasm in an inactive state by an inhibitory subunit called I.kappa.Ba. The phosphorylation of I.kappa.B and its subsequent degradation allows translocation of NF-.kappa.B to the nucleus. This activation is induced by many agents, such as inflammatory cytokines (e. g., tumor necrosis factor (TNF), lymphotoxin (LT), and interleukin (IL)-1), mitogens, bacterial products, protein synthesis inhibitors, oxidative stress (H2 O2), ultraviolet light, and phorbol esters. Agents that can downmodulate the activation of NF-.kappa.B may be used for therapeutic treatment for these pathological conditions. The present invention is drawn to several such agents. One agent is caffeic acid (3, 4-dihydroxy cinnamic acid) phenethyl ester (CAPE), a structural relative of flavonoids that is an active component of propolis from honeybee hives. It has antiviral, anti-inflammatory, and immunomodulatory properties, and has been shown to inhibit the growth of different types of transformed cells (see Grunberger, et al., Experientia 44:230-32 (1988); Burke, et al., J. Med. Chem. 38:4171-78(1995); Su, et al., Cancer Res. 54:1865-70 (1994); Su, et al., Mol. Carcinog. 4:231-42 (1991); Hlandon, et al., Arzneim.-Forsch./Drug Res. 30:1847-48 (1980); and Guarini, L., et al., Cell. Mol. Biol. 38:513-27 (1992)). In transformed cells, CAPE alters the redox state and induces apoptosis. Further, it has been reported that CAPE suppresses lipid peroxidation; displays antioxidant activity; and inhibits ornithine decarboxylase, protein tyrosine kinase, and lipoxygenase activities. CAPE can also inhibit phorbol ester-induced H2 O2 production and tumor promotion (see Bhimani, et al. , Cancer Res. 53:4528-33 (1993) and Frenkel, et al., Cancer Res. 53:1255-61 (1993)). Another such downmodulating agent presented in this disclosure is capsaicin. Capsaicin is a homovanillic acid derivative (8-methyl-N-vanillyl-6-nonenamid) with a molecular weight of 305.42. It is an active component of the red pepper of the genus Capsicum, and has been used in humans for topical treatment of cluster headache, herpes zoster, and vasomotor rhinitis (see Holzer, P., Pharmacol. Rev. 43:143 (1994); Sicuteri, et al., Med. Sci. Res. 16:1079 (1988); Watson, et al., Pain 33:333 (1988); Marabini, et al., Regul. Pept. 22:1 (1988)). In vitro capsaicin modulates cellular growth, collagenase synthesis, and prostaglandin secretion from rheumatoid arthritis synoviocytes (see Matucci-Cerinic, et al., Ann. Rheum. Dis. 49:598 (1990)). Capsaicin has also been shown to be simmunomodulatory as indicated by its ability to modulate lymphocyte proliferation, antibody production, and neutrophil chemotaxis (see Nilsson, et al., J. Immunopharmac. 10:747 (1988); Nilsson, et al., J Immunopharmac. 13:21 (1991); and Eglezos, et al, J Neuroimmunol. 26:131 (1990)). These effects play an important role in capsaicin's use for treatment of arthritis. In addition, capsaicin induces mitochondrial swelling, inhibits NADH oxidase, induces apoptosis of transformed cells, stimulates adenylate cyclase, activates protein kinase C, inhibits superoxide anion generation and alters the redox state of the cell. Various effects of capsaicin are mediated through a specific cellular receptor referred to as vanilloid receptor that is shared by resiniferatoxin. Like capsaicin, resiniferatoxin is an alkaloid derived from plants of the genus Euphorbia. Resiniferatoxin is a structural homologue of capsaicin (see FIG. 1). Resiniferatoxin is also structurally similar to phorbol esters (phorbol myristate acetate), which interacts with distinct binding sites and activates protein kinase C (see Szallasi, et al., Neurosci. 30:515 (1989); and Szallasi and Blumberg, Neurosci. 30:515 (1989)). Unlike resiniferatoxin, capsaicin has no homology to phorbol myristate acetate, but like resiniferatoxin, it too activates protein kinase C, suggesting that the latter activation is not due to the phorbol ester-like moiety on resiniferatoxin. Resiniferatoxin has been shown to mimic many of the actions of capsaicin. Thus, inhibition of nuclear transcription factor NF-.kappa.B by Caffeic Acid Phenethyl Ester (CAPE); a 2,5-hydroxy derivative of CAPE; a 5, 6-dihydroxy, bicyclic derivative of CAPE, Capsaicin (8-methyl-N-vanillyl-6-nonenamide), and Resiniferatoxin is unknown in the prior art. The inhibition of NF-.kappa.B is an important step in the treatment of various pathological conditions which result from the activation of NF-.kappa.B by inflammatory cytokines, mitogens, oxidative stress, phorbol esters and other agents. The present invention fulfills a long-standing need and desire in the art to treat such pathological conditions. SUMMARY OF THE INVENTION One object of the present invention is to provide methods of inhibition of the activation of NF-.kappa.B using various inhibitory agents. In an embodiment of the present invention, there is provided the inhibitory agent Caffeic Acid Phenethyl Ester (CAPE). In an additional embodiment of the present invention, there is provided as an inhibitor of NF-.kappa.B, a 2,5-dihydroxy derivative of Caffeic Acid Phenethyl Ester (CAPE). In yet another embodiment of the present invention, there is provided as an inhibitor of NF-.kappa.B, a bicyclic, 5, 6-dihydroxy derivative of Caffeic Acid Phenethyl Ester (CAPE). In an additional embodiment of the present invention, there is provided the inhibitory agent Capsaicin (8-methyl-N-vanillyl-6-nonenamide). In yet another embodiment of the present invention, resiniferatoxin is provided as an inhibitor of NF-.kappa.B. An additional object of the present invention is to provide methods for treating a pathological condition caused by the activation of NF-.kappa.B in an individual, comprising the step of administering caffeic acid phenethyl ester (CAPE), a 5, 6-bicyclic dihydroxy derivative of CAPE, a 2, 5-dihydroxy derivative of CAPE, capsaicin (8-methyl-N-vanillyl-6-nonenamide), or resiniferatoxin to an individual to be treated. Various embodiments of this aspect of the invention include providing methods for treating a pathological condition such as toxic/septic shock, graft vs. host reaction, acute inflammatory conditions, acute phase response, viral infection, radiation damage susceptibility, atherosclerosis, and cancer, comprising the step of administering caffeic acid phenethyl ester (CAPE); a 2, 5-dihydroxy derivative of CAPE; a bicyclic 5, 6-dihydroxy derivative of CAPE; capsaicin (8-methyl-N-vanillyl-6-nonenamide); or resiniferatoxin to an individual to be treated. Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention. These embodiments are given for the purpose of disclosure. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1. Dose response and kinetics of inhibition of TNF-dependent NF-.kappa.B by CAPE is shown. 1A: U937 cells (2×106 /ml) were preincubated at 37° C. for 2 hours with the indicated concentrations of CAPE followed by a 15- minute incubation with 0.1nM TNF. 1B upper panel: For supershift and specificity analysis of NF-.kappa.B activation, nuclear extracts were prepared from untreated or TNF (0.1 nM)-treated cells, incubated for 30 minutes with antibodies, then assayed for NF-.kappa.B. 1B lower panel: Cells were preincubated at 37° C. with 25 µg/ml CAPE for different times and then tested for NF-.kappa.B activation at 37° C. for 15 minutes either with or without 0.1 nM TNF. (-) indicates CAPE was present before the addition of TNF, (0) indicates co-incubation with TNF, and (+) indicates CAPE was added after TNF. After these treatments, nuclear extracts were prepared and assayed for NF-.kappa.B. The arbitrary units represent the relative amounts of radioactivity present in respective bands. FIG. 2: Demonstrated is the effect of CAPE on phorbol myristate acetate-, ceramide-, okadaic acid- and H2 O2 -mediated activation of NF-.kappa.B. U937 cells (2×106 /ml) were preincubated for 120 minutes at 37° C. with CAPE (25 µg/ml) followed by treatments at 37° C. with either phorbol myristate acetate (100 ng/ml for 60 minutes); or H2 O2 (0.5 mM for 30 minutes) or ceramide-C8 (10 µM for 30 minutes) or okadaic acid (500 nM for 30 minutes) and then tested for NF-.kappa.B activation. The electrophoretic mobility shift assay run for phorbol myristate acetate mediated activation was separate from the others. FIG. 3: Shown is the effect of CAPE on the binding of NF-.kappa.B to DNA. For 3A, nuclear extracts prepared from TNF activated U937 cells were incubated at 37° C. with indicated concentrations of CAPE for 30 minutes, then analyzed for NF-.kappa.B activation. For 3B, cytoplasmic extracts from untreated cells were treated with deoxycholate in the presence or absence of indicated concentrations of CAPE and analyzed for NF-.kappa.B activation. FIG. 4: Shown is the effect of CAPE on AP-1, Oct-1 and TFII D transcription factors. Cells were treated with 25 µg/ml of CAPE for 2 hours at 37° C., and nuclear extracts were prepared and used for the electrophoretic mobility shift assays. FIG. 5: The effect of CAPE on TNF-induced degradation of I.kappa.Ba and on the level of p65 in the cytoplasm and nucleus is shown. U937 cells (2×106/ ml) pretreated for 2 hours at 37° C. with or without CAPE (25 µg/ml) were incubated for different times with and without TNF (0.1 nM), then assayed for I.kappa.Ba (upper panel). For p65 (lower panel), cells pretreated for 2 hours at 37° C. with or without CAPE (25 µg/ml) were incubated for 15 minutes with and without TNF (0.1 nM), and nuclear and cytoplasmic extracts were prepared and assayed for p65 by western blot analysis. FIG. 6: The effect of DTT, BME and DMP on the CAPE-induced inhibition of NF-.kappa.B activation is shown. U-937 cells (2×106/ m1) were incubated for 2 hours with DTT (100 µM), BME (142 µM) or DMP (100 µM) in the presence or absence of CAPE (25 µg/ml), activated with TNF (0.1 nM) for 15 minutes, then assayed for NF-.kappa.B activation. FIG. 7: Shown are the structures of different analogues of CAPE (7A) and their effect on TNF-induced NF-.kappa.B activation (7B). U-937 cells (2×106/ ml) were incubated for 2 hours with different analogues of CAPE (25 µg/ml) at 37° C. , activated either with (upper panel) or without (lower panel) TNF (0.1 nM) for 15 minutes, and assayed for NF-.kappa.B activation. C denotes TNF treatment only and P denotes treatment with parent compound CAPE followed by TNF. The arbitrary units represent the relative amounts of the radioactivity present. FIG. 8: Shown is the homology in the chemical structure of capsaicin, resiniferatoxin and phorbol myristate acetate. FIG. 9: Shown are the reseutls of electrophoretic mobility shift assays demonstrating the dose response and kinetics of capsaicin for the inhibition of TNF-dependent NF-.kappa.B. 9A: ML-1a cells (2×106 /ml) were preincubated at 37° C. for 2 hours with different concentrations of capsaicin and then for 15 minutes with or without 0.1 nM TNF. 9B: Cells (2×106 /ml) were preincubated at 37° C. for 2 hours with 300 µM capsaicin and then tested for NF-.kappa.B activation at 37° C. for 15 minutes with different concentrations of TNF as indicated. 9C: ML-1a cells (2×106 /ml) were preincubated at 37° C. with 300 µM capsaicin for different times and then tested for NF-.kappa.B activation at 37° C. for 15 minutes with 0.1 nM TNF. (-) indicates time capsaicin was present before the addition of TNF, (0) indicates co-incubation with TNF, and (+) indicates time capsaicin was added after TNF. After these treatments, nuclear extracts were prepared and assayed for NF-.kappa.B. FIG. 10: Shown is the dose response of inhibition of TNF-dependent NF-.kappa.B activation by resiniferatoxin. Cells (2×106 /ml) were preincubated at 37° C. for 2 hours with different concentrations of resiniferatoxin as indicated, activated at 37° C. for 30 minutes with 0.1 nM of TNF, then tested for NF-.kappa.B. After these treatments, nuclear extracts were prepared and then assayed for NF-.kappa.B. UT stands for untreated cells. FIG. 11: Super-shift assay and specificity of the effect of capsaicin on the NF-kB activation. For panel (A), nuclear extracts were prepared from untreated or TNF-treated (0.1 nM) cells (2×106 /ml), incubated for 30 minutes with antibodies and then assayed for NF-.kappa.B. For panel (B), cells were treated with different concentrations of capsaicin for 2 hours and with TNF for 15 minutes, cytoplasmic extracts were prepared, and these extracts were treated with 8% deoxycholate and assayed for NF-.kappa.B by electrophoretic mobility shift assay. For panel (C), nuclear extracts from TNF-treated cells were incubated with different concentrations of capsaicin for 15 minutes and analyzed for NF-.kappa.B by electrophoretic mobility shift assay. FIG. 12: Shown is the effect of capsaicin on different activators (phorbol myristate acetate and okadaic acid) of NF-.kappa.B. For panel 12A, ML-1a cells (2×106 /ml) were preincubated for 2 hours at 37° C. with capsaicin, treated with either phorbol myristate acetate (25 ng/ml) or okadaic acid (500 nM) or TNF (0.1 nM) for 30 minutes, and then tested for NF-.kappa.KB activation. 100-fold excess of cold or mutated oligonucleotide was used to determine the specificity of binding. For the lane labeled as Mut. probe, mutated probe was labeled and then used to test the binding. For panel 12B, U-937 or Hela cells (2×106 /ml) were preincubated for 2 hours at 37° C. with indicated concentration of capsaicin followed by TNF (0.1 nM) for 15 minutes, and then tested for NF-kB. FIG. 13: The effect of capsaicin on TNF-induced degradation of I.kappa.Ba and on the level of p65 is shown. 13A: ML-1a (2×106/ ml) cells either untreated or pretreated for 2 hours with 300 uM capsaicin at 37° C. were incubated for different times with TNF (0.1 nM), then assayed for I.kappa.Ba in cytosolic fractions by western blot analysis. S and N represent slow- and normal-migratory bands. 13B: Cells were treated with capsaicin for different time periods then assayed for either I.kappa.Ba or p65 in cytosolic fraction by western blot analysis. 13C: ML-1a (2×106/ ml) cells pretreated for 2 hours with capsaicin were incubated with TNF (0.1 nM) for 30 minutes, then nuclear and cytoplasmic extracts were assayed for p65 by Western blot analysis. 13D: Cells were pretreated with different concentrations of capsaicin for 2 hours followed by treatment with or without TNF (0.1 nM) for 15 minutes, then cytosolic fractions were assayed for either p50 or c-Rel by western blot analysis. FIG. 14: Shown is the effect of capsaicin on the acitivity of I.kappa.Ba promoter linked to the CAT gene. Cells were transiently transfected with pI.kappa.BCAT and pmutI.kappa.BCAT, treated with 300 µM capsaicin for 2 hours, exposed to 0.1 nM TNF for 1 hour, and assayed for CAT activity. Results are expressed as fold activity over the untreated control. The appended drawings have been included herein so that the above-recited features, advantages and objects of the invention will become clear and can be understood in detail. These drawings form a part of the specification. It is to be noted, however, that the appended drawings illustrate preferred embodiments of the invention and should not be considered to limit the scope of the invention. DETAILED DESCRIPTION OF THE INVENTION It will be apparent to one skilled in the art that various substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of said invention. As used herein, the term "nuclear factor NF-.kappa.B" or "NF-.kappa.B" shall refer to the protein specific to B cells that binds to a specific DNA sequence (5-GGGGACTTTCC-3) within the immunoglobin light chain .kappa. locus enhancer region, and in mammals is a heterodimer consisting of p50 and p65 (Rel-A) proteins. NF-.kappa.B plays a central role in various responses, leading to host defense through rapid induction of gene expression, and controls the expression of various inflammatory cytokines, the major histocompatibility complex genes, and adhesion molecules involved in tumor metastasis. As used herein, the term "CAPE" shall refer to caffeic acid (3, 4-dihydroxy cinnamic acid) phenethyl ester. As used herein, the term "5, 6- dihydroxy, bicyclic derivative of CAPE" shall refer to the CAPE analogue molecule presented at FIG. 7A compound no. 6. As used herein the term "2, 5-dihydroxy derivative of CAPE" shall refer to the CAPE analogue molecule presented at FIG. 7A compound no. 1. As used herein, the term "capsaicin" shall refer to a homovanillic acid derivative, 8-methyl-N-vanillyl-6-nonenamid, with a molecular weight of 305.42. As used herein, the term "resiniferatoxin" shall refer to the structural homologue of capsaicin shown in FIG. 8B. As used herein, the term "pathological condition" shall refer to conditions that relate to or are caused by disease. Such conditions may include, but are not limited to, toxic or septic shock, graft vs. host reaction, acute inflammatory conditions, acute phase response, viral replication, radiation damage, atherosclerosis, and cancer. As used herein, the term "therapeutically effective amount" of an agent shall refer to an amount of that agent which is physiologically significant and imaproves an individual's health. An agent is "physiologically significant" if its presence results in a change in the physiology of the recipient human. For example, in the treatment of a pathological condition, administration of an agent which relieves or arrests further progress of the condition would be considered both physiologically significant and therapeutically effective. As used herein, the term "CAT" shall refer to chloramphenicol acetyltransferase. The present invention is directed to methods of inhibition of the activation of NF-.kappa.B using various inhibitory agents. It is contemplated additionally that methods for treating a pathological condition in an individual caused by the activation of NF-.kappa.B are presented. For the therapeutic applications, a person having ordinary skill in the art of molecular pharmacology would be able to determine, without undue experimentation, the appropriate dosages and routes of administration of the novel inhibitors of the activation of NF-.kappa.B of the present invention. The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion: EXAMPLE 1 Materials Penicillin, streptomycin, RPMI 1640 medium, and fetal calf serum were obtained from GIBCO (Grand Island, N.Y.). Phorbol ester and bovine serum albuminutes were obtained from Sigma Chemical Co. (St. Louis, Mo.). Bacteria-derived recombinant human TNF, purified to homogeneity with a specific activity of 5×107 units/mg, was kindly provided by Genentech, Inc. (South San Francisco, Calif.). Antibody against I.kappa.Ba, cyclin D1, and the NF-.kappa.B subunits p50 and p65 and double-stranded oligonucleotides having AP-1 and Oct-1 consensus sequences were obtained from Santa Cruz Biotechnology (Santa Cruz, Calif.). Ceramide (C8) was obtained from Calbiochem (San Diego, Calif.). Tris, glycine, NaCl, SDS, resiniferatoxin, phorbol myristate acetate, chloramphenicol, and bovine serum albumin were obtained from Sigma Chemical Co. (St. Louis, Mo.). 32 P-labeled γ-ATP with a specific activity of 7000 Ci per mmole was obtained from ICN (Costa Mesa, Calif.). Okadaic acid (OA) was obtained from LC Laboratories (Woburn, Mass.), capsaicin from Tocris Cookson Inc. (St. Louis, Mo.), acetyl coenzyme A from Pharmacia Biotech (Alameda, Calif.), and tritiated acetyl coenzyme A from Amersham Life Sciences (Arlington Heights, Ill.). The GIBCO-BRL calcium phosphate transfection system-kit (Cat. #18306-019) was obtained from Life Technologies (Madison, Wis.). CAPE and its Analogue For structure-activity relationship studies, several analogues of CAPE were synthesized as described by Grunberger, et al., Experientia 44:230-32 (1988) and Burke, et al, J. Med. Chem. 38:4171-78 (1995). These analogues included ring substituents, ester groups, rotationally constrained variants and saturated amide analogues. Stock solutions of CAPE and its analogues were made in 50% ethanol at 1-5 mg/ml and further dilutions were made in cell culture medium. Cell Lines For the CAPE studies, the human histiocytic cell line U937 cells were grown routinely in RPMI 1640 medium supplemented with glutamine (2 mM), gentamicin (50 mg/ml), and fetal bovine serum (FBS) (10%). The cells were seeded at a density of 1×105 cells/ml in T25 flasks (Falcon 3013, Becton Dickinson Labware, Lincoln Park, N.J.) containing 10 ml of medium and grown at 37° C. in an atmosphere of 95% air and 5% CO2. Cell cultures were split every 3 or 4 days. Occasionally, cells were tested for mycoplasma contamination using the DNA-based assay kit purchased from Gen-Probe (San Diego, Calif.). Studies with capsaicin and resiniferatoxin were performed with ML-1a, a human myelomonoblastic leukemia cell line kindly provided by Dr. Ken Takeda (Showa University, Japan); and U937 and HeLa cell lines, which were obtained from ATCC. The cells were grown routinely in RPMI 1640 medium supplemented with glutamine (2 mM), gentamicin (50 mg/ml), and fetal bovine serum (FBS) (10%). The cells were seeded at a density of 1×105 cells/ml in T25 flasks (Falcon 3013, Becton Dickinson Labware, Lincoln Park, N.J.) containing 10 ml of medium and grown at 37° C. in an atmosphere of 95% air and 5% CO2. Cell cultures were split every 3 or 4 days. DNA Constructs I.kappa.Ba plasmid, pI.kappa.BCAT containing a 0.2 kb upstream fragment linked to the chloramphenicol acetyltransferase (CAT) gene, and a plasmid pmutI.kappa.BCAT also containing the 0.2 kb fragment but with a mutated NF-.kappa.B site linked to CAT, were kindly supplied by Dr. Paul Chiao of the M. D. Anderson Cancer Center, Houston, Tex. The characterization of these plasmids has been described in detail in Schreiber, et al., Nucleic Acids Res. 17:6419 (1989). EXAMPLE 2 Electrophoretic Mobility Shift Assays These assays were carried out as described in detail previously by Chaturvedi, et al., J. Biol. Chem. 269:14575-83 (1994); and Schreiber, et al., Nucleic Acids Res. 17:6419 (1989). Briefly, 2×106 cells were washed with cold phosphate-buffered saline (PBS) and suspended in 0.4 ml of lysis buffer (10 mM HEPES pH 7.9, 10 mM KCl, 0.1 mM EDTA, 0.1 mM EGTA, 1 mM DTT, 0.5 mM PMSF, 2.0 mg/ml leupeptin, 2.0 mg/ml aprotinin, and 0.5 mg/ml benzamidine). The cells were allowed to swell on ice for 15 minutes, after which 12.5 ml of 10% NP-40 was added. The tube was then vortexed vigorously for 10 seconds, and the homogenate was centrifuged for 30 seconds. The nuclear pellet was resuspended in 25 µl ice-cold nuclear extraction buffer (20 mM HEPES pH 7.9, 0.4 M NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM DTT, 1 mM PMSF, 2.0 mg/ml leupeptin, 2.0 mg/ml aprotinin, and 0.5 mg/ml benzamidine), and incubated on ice for 30 minutes with intermittent mixing. Samples were centrifuged for 5 minutes at 4° C., and the supernatant (nuclear extract) was either used immediately or stored at -70° C. The protein content was measured by the method of Bradford, M. M., Anal. Biochem. 72:248-254 (1976). Electrophoretic mobility shift assays were performed by incubating 4 mg of nuclear extract with 16 fmoles of 32 P end-labeled, 45-mer double-stranded NF-.kappa.B oligonucleotide from the HIV-LTR: 5'-TTGTTACAAGGGACTTTCCGCTGGGGACTTTCCAGGGAGGCGTGG-3', (Nabel, G. and Baltimore, D., Nature 326:711-13 (1987)) for 15 minutes at 37° C. The incubation mixture included 2-3 mg of poly-(dI-dC) in a binding buffer (25 mM HEPES pH 7.9, 0.5 mM EDTA, 0.5 mM DTT, 1% NP-40, 5% glycerol, and 50 mM NaCl). The DNA-protein complex formed was separated from free oligonucleotide on a 4.5% native polyacrylamide gel using buffer containing 50 mM Tris, 200 mM glycine pH 8.5, and 1 mM EDTA, and the gel then was dried. A double-stranded mutated oligonucleotide: 5'-TTGTTACAACTCACTTTCCGCTGCTCACTTTCCAGGGAGGCGTGG-3', was used to examine the specificity of binding of NF-.kappa.B to the DNA. The specificity of binding was also examined by competition with the unlabeled oligonucleotide. For supershift assays, nuclear extracts prepared from TNF-treated cells were incubated with the antibodies against either p50 or p65 subunits of NF-.kappa.B for 30 minutes at room temperature before the complex was analyzed by electrophoretic mobility shift assay (Singh, S. and Aggarwal, B. B, J. Biol. Chem. 270:10631-39 (1995)). Antibody against cyclin D1 was included as a negative control. The electrophoretic mobility shift assays for AP-1, TFII D and Oct-1 were performed as described for NF-.kappa.B, using 32 P end-labeled double-stranded oligonucleotides. Specificity of binding was determined routinely by using an excess of unlabeled oligonucleotide for competition as described by Singh, S. and Aggarwal, B. B, J. Biol. Chem. 270:10631-39 (1995). Visualization and quantitation of radioactive bands was carried out by phosphorimager (Molecular Dynamics, Sunnyvale, Calif.) using `Image-quant` software. EXAMPLE 3 Western Blotting for I.kappa.Ba and p65 After the NF-kB activation reaction, postnuclear extracts were resolved on 10% SDS-polyacrylamide gels for I.kappa.Ba. To determine p65 levels, nuclear and postnuclear (cytoplasmic) extracts were resolved on 8% SDS-polyacrylamide gels. Proteins were then electrotransferred to Immobilon P membranes, probed with a rabbit polyclonal antibody against I.kappa.Ba or against p65, and detected by chemiluminescence (ECL-Amersham; 30). EXAMPLE 4 Effect of CAPE on the Activation of the Transcription Factor NF-kB U937 cells were used for these studies since the response of U937 cells to NF-.kappa.B activation by various stimuli has been well characterized (see Reddy, et al., J. Biol. Chem. 269:25369-72 (1994)). Cell viability of greater than 98% was obtained with all concentrations of CAPE and its analogues in these experiments. U937 cells were preincubated for 2 hours with different concentrations of CAPE, treated with TNF (0.1 nM) for 15 minutes at 37° C., then examined for NF-.kappa.B activation. Results (FIG. 1A) indicate that CAPE inhibited the TNF-dependent activation of NF-.kappa.B in a dose-dependent manner, with the maximum effect occuring at 25 µg/ml. No activation of NF-.kappa.B was noted in untreated cells or those treated with either the vehicle (ethanol) alone or with CAPE alone. To show that the retarded band observed by electrophoretic mobility shift assay in TNF-treated cells was indeed NF-.kappa.B, nuclear extracts were incubated with antibodies to either p50 (NF-.kappa.B1) or p65 (Rel A) subunits in separate treatments followed by electrophoretic mobility shift assay. The results from this experiment (FIG. 1B, upper panel) show that antibodies to either subunit of NF-.kappa.B shifted the band to higher molecular weight, suggesting that the TNF-activated complex consisted of p50 and p65 subunits. Nonspecific antibody against cyclin D had no effect on the mobility of NF-.kappa.B. In addition, the retarded band observed by electrophoretic mobility shift assay in TNF-treated cells disappeared when unlabeled oligonucleotide (100-fold in excess) was used but not when the mutated oligonucleotide was used (FIG. 1B, upper panel). The kinetics of inhibition was examined by incubating the cells with CAPE for 120, 90, 60, and 30 minutes before the addition of TNF, simultaneously with the addition of TNF, and 5 and 10 minutes after the addition of TNF. The cells were treated with TNF for 15 minutes. TNF response was inhibited only when the cells were pretreated with CAPE (FIG. 1B, lower panel). Cotreatment of cells with TNF and CAPE was not effective. EXAMPLE 5 CAPE also Blocks NF-.kappa.B Activation Induced by Phorbol Ester, Ceramide, Okadaic Acid and Hydrogen Peroxide NF-.kappa.B activation is also induced by phorbol ester (phorbol myristate acetate), ceramide, okadaic acid and hydrogen peroxide (Meyer, et al., EMBO J. 12:2005-15 (1993)). However, the initial signal transduction pathways leading to the NF-.kappa.B activation induced b y these agents differ. The effect of CAPE on the activation of the transcription factor by these various agents was therefore examiner. The results shown in FIG. 2 indicate that CAPE completely blocked the activation of NF-.kappa.B induced by all four agents. These results suggest that CAPE acts at a step where all these agents converge in the signal transduction pathway leading to NF-.kappa.B activation. EXAMPLE 6 CAPE Inhibits DNA Binding of NF-.kappa.B Specifically and not Other Transcription Factors Both TPCK, a serine protease inhibitor, and herbimycin A, a protein tyrosine kinase inhibitor, have been shown to block the activation of NF-.kappa.B by their interference with the binding of NF-.kappa.B to DNA (Finco, et al., Proc. Natl. Acad. Sci. U.S.A. 91:11884-88 (1994); and Mahon, T. M. and O'Neill, L. A. J., J. Biol. Chem. 270:28577-64 (1995)). To determine the effect of CAPE on the binding of NF-.kappa.B to DNA, the nuclear extracts from TNF-preactivated cells were incubated with various concentrations of CAPE. Electrophoretic mobility shift assays (FIG. 3, upper panel) showed that CAPE prevented NF-.kappa.B from binding to DNA. Since I.kappa.Ba can also be dissociated from NF-.kappa.B by a mild treatment with detergent such as deoxycholate, the ability of deoxycholate-treated cytoplasmic extracts to bind to the DNA with or without CAPE treatment was examined. Here, too, CAPE interfered with the binding of NF-.kappa.B proteins to DNA (FIG. 3, lower panel). The ability of CAPE to inhibit the binding of other transcription factors such as AP-1, TFII D and Oct-1 was tested. The effect of CAPE on NF-.kappa.B binding was specific, as it did not inhibit the DNA-binding ability of the other transcription factors (FIG. 4) EXAMPLE 7 CAPE Does Not Inhibit TNF-dependent Phosphorylation and Degradation of I.kappa.Ba The translocation of NF-.kappa.B to the nucleus is preceded by the phosphorylation and proteolytic degradation of I.kappa.Ba (see Thanos, D. and Maniatis, T., Cell 80:529-32 (1995)). To determine whether the inhibitory action of CAPE was due to an effect on I.kappa.Ba degradation, the cytoplasmic levels of I.kappa.Ba protein were examined by western blot analysis. As shown in FIG. 5 upper panel, treatment of cells with CAPE had no effect on the cytoplasmic pool of I.kappa.Ba, but treatment of cells with TNF decreased the I.kappa.Ba band within 5 minutes and completely eliminated it in 15 minutes; the band then reappeared by 30 minutes. The presence of CAPE did not affect significantly the TNF-induced rate of degradation of I.kappa.Ba but it did delay its resynthesis. This delay may be a feedback regulation, as the resynthesis of I.kappa.Ba is dependent on NF-.kappa.B activation. Because NF-.kappa.B activation requires nuclear translocation of the p65 subunit of NF-.kappa.B, the cytoplasmic and nuclear pool of p65 protein was examined by western blot analysis. As shown in FIG. 5 lower panel, none of the treatments altered significantly the cytoplasmic pool of p65, but the TNF-induced appearance of p65 in the nucleus was blocked by CAPE. The decrease in the corresponding cytoplasmic pool of p65 in TNF-treated cells was not significant, perhaps because upon activation, only 20% of p65 is translocated to the nucleus. EXAMPLE 8 Reducing Agents Reverse the Effect of CAPE It has been shown that the biological effects of pervanadate, TPCK and herbimycin A on suppression of NF-.kappa.B activation can be reversed by reducing agents. Therefore, the ability of DTT, 2, 3-dimercaptopropanol (DMP), and beta mercaptoethanol (BME) to reverse the effect of CAPE was examined. Cells were treated with CAPE in the presence and absence of either DTT or DMP or BME and examined for the activation of NF-.kappa.B by TNF. As shown in FIG. 6, none of the reducing agents by themselves had a significant effect on TNF-dependent activation of NF-.kappa.B, but all reducing agents reversed completely the inhibition induced by CAPE. These results implicate the critical role of sulfhydryl groups in the TNF-dependent activation of NF-.kappa.B. EXAMPLE 9 Structure/Activity Relationship Studies on CAPE To delineate further the role of CAPE in inhibition of NF-.kappa.B activation, analogues of CAPE with four different types of modifications were used. These analogues included ring substituents (compounds 1, 2, 3), ester groups (compound 4), rotationally constrained variants (compounds 5 and 6), and saturated amide analogues (compound 7 and 8), all shown in FIG. 7A. These analogues have been characterized previously for their ability to inhibit human HIV integrase and cell growth (see Burke, et al., J. Med. Chem. 38:4171-78 (1995)). Although all the compounds were active in inhibiting NF-.kappa.B activation, there were marked variations in their inhibitory ability (FIG. 7B). Alteration of the hydroxyl group placement from 3,4-dihydroxy pattern to 2,5-dihydroxy pattern (compound 1) increased the potency of inhibition over that resulting from replacement of the hydroxyl groups of CAPE with two methyl ethers (compound 2). However, addition of a third hydroxyl group to give 2,3,4-trihydroxy derivative (compound 3) resulted in a loss of potency, suggesting that the number and the placement of hydroxyl groups is a critical determinant of the extent of inhibition. In the group of ester analogues, the caffeic acid portion of the molecule (3,4-dihydroxycinnmic acid) was held constant and the phenylethyl side chain was varied. An increase in the length of the alkyl spacer (compound 4) resulted in a significant loss of inhibition. In the rotationally constrained variants, bicyclic analogues of two isomers of CAPE that differed in the placement of hydroxyl substituents were used. A drastic change in the inhibitory potency of the two analogues was seen. The isomer- 5 was completely ineffective, whereas the isomer- 6 completely abolished the binding, once again indicating that the placement of the hydroxyl groups plays a critical role in inhibiting NF-.kappa.B activation. In the saturated amide analogues, the importance of the side chain bond and the ester oxygen was examined. The analogue with three additional hydroxyls in the (phenylethyl) amine ring (compound 7) and the reverse amide analogue (compound 8), which lacked an additional hydroxyl group, were less active than CAPE. Thus, structural analogues of CAPE may be more active than CAPE (e.g., compound 6), as active as CAPE (e.g., compound 1), and less active than CAPE (e.g., compounds 2, 3, 4, 5, 7, and 8). EXAMPLE 10 Transient Transfection and CAT Assays HeLa cells were transiently transfected with pI.kappa.BCAT and pmutI.kappa.BCAT for 20 hours by the calcium phosphate method according to the instructions supplied by the manufacturer (GIBCO-BRL). After transfection, the medium (MEM) was replaced; cells were incubated for 24 hours at 37° C. then treated with capsaicin (300 uM) for 2 hours before stimulation with 0.1 nM TNF for 1 hour. Thereafter, cells were washed with phosphate-buffered saline and examined for CAT activity as described (Sambrook J., E. E. Fritsch, and T. Maniatis. (eds), Molecular cloning: A laboratory manual, 2d Ed. Cold Spring Harbor Press., N. Y.). EXAMPLE 11 Capsaicin Inhibits TNF-dependent Activation of NF-.kappa.B The effect of capsaicin and its analogue resiniferatoxin which is also structurally homologous to phorbol ester (see FIG. 8) were tested for their ability to modulate NF-.kappa.B activation. The maximum time of incubation and the concentration of the compounds used had minimal effect on cell viability or on the TNF receptors. Upon exposure of cells for 2 hours to 100 µM, 200 µM and 300 µM capsaicin, the cell viability, as determined by trypan blue exclusion, was 99%, 98% and 95%, respectively. ML-1a cells were pretreated with different concentrations of capsaicin (up to 300 µM) for 2 hours, incubated either with or without TNF (0.1 nM) for 15 minutes at 37° C., and examined for NF-.kappa.B activation by electrophoretic mobility shift assays (FIG. 9A). The results show that capsaicin by itself did not activate NF-.kappa.B, and 200-300 µM capsaicin inhibited most of the activation induced by TNF. The activation of NF-.kappa.B by TNF is quite specific as the band disappeared when unlabeled oligo was added but not when the oligo with mutated binding sites was added (see FIG. 13A). Previous studies have shown that a high concentration of TNF (10 nM) induces more robust and rapid (within 5 minutes) activation of NF-.kappa.B (Chaturvedi, et al., J. Biol. Chem. 269:14575-83 (1994)). To determine if capsaicin also could suppress a robust response to TNF, capsaicin-pretreated cells were challanged with increasing concentrations of TNF (up to 10 nM) for 15 minutes and then examined for NF-.kappa.B (FIG. 9B). Although the activation of NF-.kappa.B by 10 nM TNF was very strong, capsaicin completely inhibited it as efficiently as it did the 0.01 nM concentration. These results show that capsaicin is a very potent inhibitor of NF-.kappa.B activation. To gain further insight into the kinetics of inhibition, the cells were preincubated with capsaicin for 120, 60, 30, and 10 minutes and then exposed to TNF. Capsaicin was also added simultaneously (0 minutes) and 10 minutes after the addition of TNF. In every case, TNF was present for 30 minutes. As shown in FIG. 9C, co-incubation of cells with capsaicin and TNF together did not block NF-.kappa.B activation. The maximum inhibition of the response to TNF was noted only when cells were pre-incubated for 120 minutes with capsaicin. EXAMPLE 12 Resiniferatoxin Also Blocks NF-.kappa.B Activation Resiniferatoxin is a structural analogue of capsaicin and both share a common receptor (see Holzer, H. , Pharmacol. Rev. 43:143 (1994); and Szallasi, A., and Blumberg, P., Brain Res. 524:106 (1990)). Therefore, the ability of resiniferatoxin to inhibit TNF-mediated NF-.kappa.B activation was examined. Like capsaicin, treatment of cells with resiniferatoxin by itself did not activate NF-.kappa.B, but it completely inhibited TNF-mediated activation of NF-.kappa.B in a dose-dependent manner (FIG. 10). As 40 µM of resiniferatoxin was sufficient for maximum inhibition of the TNF response, it suggests that resiniferatoxin is approximately 8-fold as potent as capsaicin. EXAMPLE 13 Activated NF-.kappa.B Inhibited by Capsaicin Consists of p50 and p65 Subunits Various combinations of Rel/NF-.kappa.B proteins can constitute an active NF-.kappa.B heterodimer that binds to specific sequences in DNA. To show that the retarded band visualized by electrophoretic mobility shift assays in TNF-treated cells was indeed NF-.kappa.B, nuclear extracts from TNF-activated cells were incubated with antibody to either p50 (NF-.kappa.B1) or p65 (Rel A) subunits and electrophoretic mobility shift assays were performed. Antibodies to either subunit of NF-.kappa.B shifted the band to a higher molecular weight (FIG. 11A), thus suggesting that the TNF-activated complex consists of both the p50 and p65 subunits. A partial shift noted with anti-p65 antibody may be due to the nature of the antibodies or the conditions used. As a control, an unrelated antibody (NS) was run; it had no effect on the NF-.kappa.B bands. It has been shown that both TPCK, a serine protease inhibitor, and herbimycin A, a protein tyrosine kinase inhibitor, downregulate NF-.kappa.B activation by chemical modification of the NF-.kappa.B subunits thus preventing NF-.kappa.B's binding to DNA. To determine if capsaicin directly modifies NF-.kappa.B proteins, DNA was incubated with either deoxycholate-treated cytoplasmic extracts from capsaicin-exposed cells (FIG. 11B) or nuclear extracts exposed to capsaicin after TNF treatment (FIG. 11C) and electrophoretic mobility shift assays were performed. The deoxycholate treatment has been shown to dissociate the I.kappa.Ba subunit, thus releasing NF-.kappa.B for binding to the DNA. The results in FIGS. 11B and 11C show that capsaicin did not modify the ability of NF-.kappa.B to bind to the DNA. Therefore capsaicin inhibits NF-.kappa.B activation through a mechanism different from that of TPCK or herbimycin A. EXAMPLE 14 Capsaicin Also Blocks NF-.kappa.B Activation Induced by Other Agents NF-.kappa.B activation is induced by a wide variety of other agents including TNF, phorbol myristate acetate and okadaic acid. However, it was not clear whether the pathway leading to the NF-.kappa.B activation is same for all these agents. Therefore, the effect of capsaicin on the activation of NF-.kappa.B by different agents was examined. Like TNF, capsaicin completely blocked phorbol myristate acetate-induced activation of NF-.kappa.B, but activation mediated through okadaic acid was inhibited only partially (FIG. 12A). EXAMPLE 15 Inhibition of NF-.kappa.B Activation by Capsaicin is not Cell Type Specific Besides ML-1a cells, the ability of capsaicin to block TNF-mediated NF-.kappa.B activation in other myeloid (U-937) and epithelial (HeLa) cells was examined. The result of these experiments, shown in FIG. 12B, indicate that capsaicin inhibited TNF-induced NF-.kappa.B in both of these cell types. Almost complete inhibition was noted at 200 µM capsaicin, thus suggesting that this effect of capsaicin is not cell type specific. EXAMPLE 16 Capsaicin Inhibits TNF-dependent Degradation of I.kappa.Ba It has been shown that upon stimulation of cells, I.kappa.Ba is phosphorylated and undergoes proteolytic degradation, thus allowing NF-.kappa.B to translocate to the nucleus. It was a goal of the present invention to determine whether the inhibitory action of capsaicin was due to prevention of I.kappa.Ba degradation. The cytoplasmic levels of I.kappa.Ba protein were examined by western blot analysis. The results shown in FIG. 13A indicate that TNF treatment of cells caused the appearance of a slower-migrating band of I.kappa.Ba within 5 minutes; and by 15 minutes I.kappa.Ba completely disappeared (upper panel). The pretreatment of cells with capsaicin, however, abolished both the appearance of TNF-mediated slower-migrating band as well as degradation of I.kappa.Ba (lower panel). The appearance of the slower-migrating band has been shown to be induced by phosphorylation of I.kappa.Ba at serine 32 and 36 (see Finco, et al., Proc. Natl. Acad. Sci. U.S.A. 91:11884-88 (1994)). The level of p65 and I.kappa.Ba in the cytoplasm of cells treated with capsaicin for different times was investigated (FIG. 13B). The levels of cytoplasmic I.kappa.Ba (upper panel) and p65 (lower panel) remained unaffected in capsaicin-treated cells. However, when the level of p65 in the cytoplasm and nucleus of cells treated with capsaicin alone or with TNF and capsaicin together or with only TNF was examined, it was found that TNF induced the migration of p65 protein into the nucleus. Capsaicin by itself did not induce this migration but it did block the TNF-induced migration. These results indicate that capsaicin does not affect the level of p65 but rather prevents its TNF-dependent translocation to the nucleus. In addition to p65, the effect of capsaicin was also examined on the cytoplasmic pool of other members of the Rel family of proteins. The results shown in FIG. 13D indicate that neither capsaicin by itself or in combination with TNF had any effect on the levels of either p50 or c-Rel proteins. EXAMPLE 17 Capsaicin Represses the I.kappa.Ba -CAT Gene Expression As the promoter of the I.kappa.Ba gene has NF-.kappa.B binding sites and is regulated upon NF-.kappa.B activation inducing within minutes rapid gene expression, a transient-expression assay was used to determine the effect of capsaicin on the TNF-induced I.kappa.Ba promoter linked to the CAT gene. As expected, almost four-fold increase in CAT activity was obtained upon stimulation with TNF (FIG. 14). However, TNF-enhanced CAT activity was reduced significantly when pI.kappa.BCAT-transfected cells were pretreated with capsaicin for 2 hours prior to TNF treatment. Transfection with an I.kappa.B promoter containing a mutated NF-.kappa.B binding site, pmutI.kappa.BCAT, did not result in induction of CAT by TNF. These results demonstrate that capsaicin can also repress the gene expression induced by NF-.kappa.B activator. Any patents or publications mentioned in this specification are indicative of the levels of those skilled in the art to which the invention pertains. Further, these patents and publications are incorporated by reference herein to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. One skilled in the art will appreciate readily that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those objects, ends and advantages inherent herein. The present examples, along with the methods, procedures, treatments, molecules, and specific compounds described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes to this invention and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention as defined by the scope of the claims. * * * * * Other References
Deal et al. "Treatment of arthrtis with topical capsaicin: A double-blind trial," Clin. Ther. (1991) 13(3):383-395.
Natarajan et al. "Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-.kappa.B," Proc. Natl. Acad. Sci. USA (Aug. 1996) 93: 9090-5.
Singh et al. "Activation of transcription factor NK-.kappa.B is suppressed by curcumin (diferulolymethane)," J. Biol. Chem. (Oct. 1995) 270(42): 24995-25000.





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