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Resiniferatoxin (RTX)

The Promise of RTX Therapy Offers New Hope for Urge Incontinence

Real Living with MS, Dec. 1998

What is Urge Incontinence?

"Physicians," explains Afferon Corporation's Terry Winters, Ph.D., "recognize a continuum starting with Urinary frequency, going through strong urge, then ending in incontinence. Therefore, the definition of Urge Incontinence is a strong, uncontrollable desire to urinate.

In persons with MS, the question concerns how much urge is actually felt; our under-standing is that these patients feel a great deal, unlike those with Spinal Cord injuries."

Dr. Winters says that there are numerous theories about Bladder control. He states that there are "two circuits for Bladder emptying": the juvenile circuit (effective when we are young), which isn't under conscious control; and a second circuit that comes into being as we grow older and over which we do have conscious control.

"The first is mediated by C fibers in the bladder," he says, "and the second is mediated by A (delta) fibers."

"The A-fiber circuit works through the Brain, where the Bladder is under conscious control. The C fibers short-circuit through the spine and do not go through the Brain." He says the theory is that Neurogenic, overactive, or urge-incontinent Bladder occurs when the C-fiber circuit is reactivated.

Researchers at the Univ of Pittsburgh are encouraged by early data for a new drug in the treatment of urge incontinence in persons with neurological diseases such as Multiple Sclerosis (MS).

Resiniferatoxin (RTX) is one of a family of compounds called Vanilloids and is chemically related to Capsaicin (CAP), the ingredient in chili peppers that makes them hot. In the past, capsaicin has been administered directly to the bladder to treat urge incontinence, but adverse effects have limited its use.

RTX didn't show unacceptable adverse effects during academic analyzes of patients or during studies conducted by Afferon Corporation, a privately held pharmaceutical company focusing on urology.

Afferon literature explains that Vanilloids act by desensitizing overactive afferent Sensory Neurons. In the first two phases of clinical trials (which did not consist of persons with MS), RTX is proving to be a potent neural desensitizing agent that acts by inhibiting the transmission of messages from peripheral sensory neurons to the Central Nervous System.

The clinical development division of Afferon is located in Wayne, PA, and researchers there say that thus far, a majority of patients enrolled have experienced significant incontinence relief.

Terry Winters, Ph.D., is chief executive officer for Afferon and is based in Scottsdale, AZ. He says that at some point, the majority of those with MS will suffer urge incontinence, and he believes RTX may be helpful.

The drug solution, he explains, is administered into the Bladder through a urinary catheter procedure performed in a doctor's office.

The patient empties his Bladder, and the drug solution is entered into the Bladder through a gravity feed and is then held there for several minutes. Local or general anesthesia has not been required, he says, and one dose is effective for 90 to 100 days.

"Capsaicin has been known and used as a drug for centuries," explains Dr. Winters. "The old pharmacies always had a jar of capsicum extract. Now, one can buy Capsaicin creams over the counter as an arthritis remedy. It's also been used as a remedy for pain."

He says the receptor for Capsaicin was recently cloned at the Univ of California at San Francisco. There it was proved that the C-fiber receptor (a class of Sensory Neurons that occur throughout the body, particularly in the Bladder) is activated not only by Capsaicin, but also by RTX and by heat.

C fibers are responsible for sensing pressure in the Bladder and transmitting that sensation to the brain. "This threw a lot of light (on the subject) and made the science credible."

Dr. Winters explains that while RTX is indeed an analogue of Capsaicin, related chemically and sharing one functional feature, it's far more potent.

    "However, these materials have two effects on nerves:
  • The first is as an irritant, and
  • the second is a desensitization effect.

With Capsaicin, the irritant effect is much stronger than the desensitization. With RTX, though, the irritation is minimal, and desensitization is about 1,000 times that of Capsaicin."

He says Afferon chose RTX because of its particular balance of desensitization versus irritation properties and because it can be manufactured easily. The raw material, he explains, is obtained from the cactus, then isolated and chemically transformed.

"We (at Afferon) decided to work on RTX in the bladder when we saw these Capsaicin results. Our technology is licensed from the National Institutes of Health, which had researchers working on peppers and their derivatives. We use RTX mostly in persons with MS but also in patients with Spinal Cord injury and stroke," explains Dr. Winters.

In clinical trials with RTX, Dr. Winters says, researchers have seen minimal adverse effects, such as a mild itching and burning. He says scientists aren't sure, however, if these adverse effects are caused by the drug or because patients are receiving something cool in their Bladders.

"Certainly," he assures, "we've seen no (adverse) effects on the order of Capsaicin's, and in addition, we've found that onset of relief is almost immediate, not transient."

Adding a caveat, Dr. Winters states that "these results are preliminary, but so far they appear very promising based upon measurements of urinary frequency, Bladder capacity, and incontinent episodes." He says the results are encouraging enough to take the drug to the next stage of clinical trials.

RTX is presently in Phase II trials in Europe and the U.S. Dr. Winters says Afferon hopes to finish Phase III clinical trials by the end of next year, after which it will file a new drug application with the FDA.

"We are carrying out three protocols at four separate centers and are in the process of signing up new centers," says Dr. Winters. "We will probably do more protocols as well." The U.S. centers are located in Pennsylvania at the Univ of Pittsburgh and at Thomas Jefferson Univ Hospital in Philadelphia.


Other drugs commonly prescribed for bladder symptoms in MS, such as oxybutynin (Ditropan) or propantheline, work to decrease the motor contractions of the bladder. A new drug, tolterodine (Detrol) also works similarly, but may have fewer side effects.

RTX, on the other hand, acts differently by increasing the sensory input to the bladder. It is conceivable that eventually both approaches may be useful together.

RTX Research Participants Share Stories

Tracy Lee Tracy first learned of RTX therapy when she attended a Chapter sponsored educational seminar on "Healthy Bladder and Bowel," back in August 1998.

Dr. Michael Chancellor, Associate Professor, Urologic Surgery, Neurourology and Urinary Incontinence, UPMC Health System, was the keynote speaker for the Quality of Life lecture.

That night, Dr. Chancellor explained the promising new therapy for urge incontinence being studied at the Univ of Pittsburgh. Tracy left the seminar encouraged and the next week called Dr. Chancellor's office, and she was enrolled in the study in the fall.

According to Tracy, prior to enrolling in the study she suffered from uncomfortable and often embarrassing urge incontinence. She utilized self-catherization every two hours and often had to return home from outings because she could not locate an accessible public facility to do this.

Today she states she "feels less urgency and catherizes every four hours, which gives her more self confidence when she is out of her home. Tracy realizes she may be in the "placebo group," but she is encouraged with the changes to date.

She also would like everyone to know that, although she has had MS for many years, "you can always learn and benefit from the ongoing educational programs the Chapter offers." See program section for further details. Call (412) 692-4081 regarding the RTX study.

Heather Rebic inadvertently learned about the RTX study when, at the recommendation of her Neurologist, she made an appointment to see Dr. Chancellor for her "disabled bladder." Heather, who is a registered nurse currently unable to work, decided to enroll in the study with the hope that she could help herself and others in the future.

Prior to her initial RTX treatment, which she describes as "an uncomfortable but not a painful procedure," she experienced a burning sensation in her bladder.

She states now that "this sensation has been decreased and there has been a dramatic prolongation in time between urination. Heather remains realistically hopeful, reminding herself that she, too, could be receiving a placebo. She also initiated treatment with the medications, Detrol and Ditropan, when she enrolled in the study and still finds it necessary to self catheterize throughout her day.

A final note regarding this therapy has to do with insurance coverage. If this treatment proves successful and achieves FDA approval, HMOs may be reluctant to pay for it, because a disabled bladder is not considered to be a life threatening condition.

Look for further details regarding RTX therapy and insurance issues in a future newsletter. For further details regarding this and other important research projects, please call Dr. Chancellor at (412) 692-4081.

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