Trial to investigate efficacy of aloe vera in patients with interstitial cystitis

"What we developed was a way in which we could eliminate all the anthraquinones, all the insoluble fiber, but stabilize the high nutrient content at the same time," says Heather Florio.

In this interview, Heather Florio and Stephen J. Walker, PhD, discuss the use of aloe vera in patients with interstitial cystitis. Florio is the CEO of Desert Harvest, and Walker is a professor at the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina.

Could you tell me about yourselves and your work with aloe vera and interstitial cystitis?

Florio: My name is Heather Florio. I'm the CEO of Desert Harvest. Desert Harvest was founded in 1993, specifically for interstitial cystitis. It was started by my parents. My aunt had interstitial cystitis and at the time, in the early 1990s, this was a very "all in your head" kind of disease in the fact that there was very little representation of it anywhere in the United States, and most urologists claimed that it was not an actual condition. When my aunt was diagnosed by one of the very few people who saw patients with interstitial cystitis in the early 1990s in this country, she had very few options; they didn't even have Elmiron [pentosan polysulfate sodium]. And so, she started to seek out natural options and went to a health products store, bought a bottle of aloe vera, took the whole bottle, and slept through the night. That led my parents to think, "Maybe there's something here."

And so, they got together with a friend who was a chemist to figure out how [the aloe vera was beneficial], because aloe vera naturally has what's called anthraquinones in it. These are latex chemicals that, long term, can be carcinogenic to the colon and cause liver and kidney damage. There are some other components to aloe vera that are not good for the body long term and in high doses. We started to look at how could we develop a formulation that was safe for long-term use and in high doses. We developed the patented formulation that we still use today.

For over 30 years, we have done clinical research. We've done questionnaire-related research with the Interstitial Cystitis Association (ICA) looking at their patient database. We have worked with hundreds of thousands of patients with interstitial cystitis worldwide for the past 30 years now. Our efficacy and our initial double-blind placebo-controlled study, although small, had an 87.5% response rate of some or complete relief of all symptoms with just taking our capsules. And then over the years, we've developed a complementary line of either supplements or pelvic health tools for our demographic, always all natural, based off aloe vera, or in the case of our tools, obviously not. But we've always been committed to this community and obviously, in the evolution of pelvic floor physical therapy, got heavily involved in that from its inception.

Walker: My name Steve Walker. I'm a basic science researcher, cross-appointed the department of urology at Atrium Wake Forest Baptist. I've worked closely with a group of urologists and urogynecologists to do a variety of studies, but primarily, we've been focused on interstitial cystitis now for the past 10 years. We are a tertiary referral center for patients with interstitial cystitis, so we get literally hundreds of new patients every year. In the past several years, we've created a clinical repository, which includes a bio repository of samples from about 600 unique patients with interstitial cystitis/bladder pain syndrome.

I'm a molecular biologist by training, and so we're looking for ways to stratify patients with interstitial cystitis into clinically meaningful subgroups, so that maybe some of the trials will demonstrate more efficacy. This is based on the premise that interstitial cystitis is highly heterogeneous. Anybody that knows much about it understands that facet. It's a term reserved for patients who have chronic pain in the pelvic region of unspecified origin for at least 6 weeks or more. Once you rule out urinary tract infections and other confusable causes, then you're often left with a diagnosis of what in this country is called interstitial cystitis/bladder pain syndrome (IC/BPS).

There have been a number of clinical trials trying different things for treating IC/BPS, and typically, the efficacy is pretty low. We believe that at least part of that is due to patient selection. This is a broadly heterogeneous patient population, and if you pick 100 patients for your trial who represent the heterogeneity within the population and your therapy targets a specific etiology or phenotype, then it's not surprising that you may only capture a very small percentage of that 100 patients in whom that particular treatment works. One of the ways to mitigate that low efficacy is to identify patient subgroups that are more similar to each other based on of a number of specific criteria. Then, when you have targeted therapies, try subsets of patients who, based on whatever characteristics you're looking at, would be more amenable to improving.

For example, if you're talking about aloe vera, which is meant to target the glycosaminoglycan (gag) layer of the bladder, then you're looking at an etiology that has to do with bladder epithelium and damage or inability to repair damage in the bladder epithelium. You would like to target this treatment to patients for which you have some evidence that there's a bladder urothelium problem, and that's one of the primary issues. There are many patients who have what we think is a systemic pain disorder and they may or may not benefit from this, but we don't know until we try. In a nutshell, that's what we do. We do patient stratification based on a combination of molecular and clinical characteristics.

We've determined that there are at least 2 subgroups within the IC/BPS patient population: those who are bladder centric, who truly have a bladder disease. Those are patients who will, more likely than not, progress to an end-stage bladder situation. Targeted treatments for that group of patients would probably be different than treatments meant to target the vast majority—80% to 85%—of all patients with IC/BPS who we think have a systemic pain disorder. Given those 2 phenotypes, we would expect for example, aloe vera, or treatments like that (instillation therapy) would probably benefit those with a non-bladder-centric phenotype, i.e., those with a systemic pain disorder phenotype.

I met Heather because she knows one of the clinicians that I work closely with. Everybody in the field knows Dr. Robert J. Evans for his work in interstitial cystitis. Heather found out about him through ICA, and so they'd known each other before I came on board. We're now doing clinical trials. My group does the molecular characterization and patient stratification and then we've now moved into doing some clinical trials, mostly non-invasive stuff, to treat patients with interstitial cystitis. And so obviously, aloe vera then is a sort of a natural progression of our work.

I didn't know anything about interstitial cystitis 8 or 9 years ago, and now I know a lot more than I did then. We've published quite a bit in patient stratification-type strategies, and we've gotten a few clinical trials underway. Again, it's mostly non-invasive therapeutics that are meant to help patients. Aloe vera is an oral therapy, but it's meant to behave, I guess, in similar ways to the instillation therapies that improve the gag layer in the bladder urothelium.

As I said, Heather had talked to Dr. Evans several years ago, and they actually put in an application to the National Institutes of Health, and then I got involved a couple years ago. We thought it was going to be smooth sailing, but the FDA had different ideas, based on what Heather pointed out regarding the anthraquinones and the preparation. And I think we just did a tactical error because the anthraquinone level in this purified freeze-dried aloe vera apparently is not detectable, but they didn't buy that, so we have to do a lot of liver function testing and so forth to make sure it's safe. We're going to do a clinical trial using Desert Harvest aloe vera and measure improvement in patients with interstitial cystitis.

Florio: That's the biggest difference. This isn't your health food store aloe vera. This isn't what you can get on Amazon. We've done liver function tests in the past, we've done blood work in multiple studies, including one that's just about ready to publish in Europe in which we did liver function testing, different things like that, because we want to be able to show the efficacy of that. That's because the FDA is going to go to the monograph of aloe vera and if you Google "aloe vera for internal use," the first thing you're going to see is "known carcinogen." This is because the aloe vera that you find in the health food stores is meant for short-term use as a digestive aid, because the FDA, years ago, did set a limit of anthraquinones—you could have 10 parts per million. That is what makes Desert Harvest so unique; we've developed a patented process. You can extract all the anthraquinones, but then you just really have expensive water at that point, because you have to irradiate it; you have to heat-treat it and you've just killed all of the active nutrients.

What we developed was a way in which we could eliminate all the anthraquinones, all the insoluble fiber, but stabilize the high nutrient content at the same time. We're utilizing the whole leaf and then extracting components. Technically, the FDA says we're not utilizing the whole leaf, so we don't call it “whole-leaf” aloe vera anymore. We use the inner and the outer leaf, and that is how we would term that, but part of our patented process is stabilizing those nutrients. The minute you cut an aloe vera leaf off, malic acid immediately begins to eat away at the nutrients and so within about 6 to 8 hours, there are no nutrients left in an aloe vera leaf, so if you've ever seen them in the grocery store, again, it's expensive water, because aloe vera is 98.5% water. It's a hydrophilic plant. One 180-capsule bottle of our super-strength aloe vera is equivalent to roughly 89 full-grown aloe barbadensis miller leaves. That's always been our biggest struggle. I almost wish I could go back 30-plus years and not call it "aloe vera." The safety concerns with that are the biggest barrier that we're constantly educating patients about.

What other products does Desert Harvest offer?

Florio: One of the things that we see, especially in our group, and we've kind of delineated in some of our questionnaire research, is that we really see 3 phentoypes, even though this hasn't been legitimately phenotyped yet, let's say, but subgroups that we see. One is bladder centric, and those are the ones who respond the best to the aloe vera. And then we have this other group that has pelvic floor, myofascial kind of pain and we know that that group responds...to pelvic floor physical therapy. And then we have this third group, which is a kind of neuralgia pain group that is usually some kind of other injury or chronic pain disorder; they have a lot of overlapping comorbidities that we see.

We've tried to focus out these groups with different products. We have the pelvic floor physical therapy tools. I wrote a book with a pelvic physical therapist, Ingrid Harm-Ernandes, P.T., W.C.S, at Duke University called "The Musculoskeletal Mystery." It's an at-home guide because one of the things we were seeing is insurance wasn't covering pelvic physical therapy a lot, and so we wanted to give options for patients to be able to do exercises at home, because the go-to is, "Oh, I just need to do my Kegels." In reality, what we mostly see in the pelvic physical therapy world is hypertonic pelvic floor. What we need to do is release those pelvic floors and then build them back up and strengthen them up. That's why we do the EZMagic pelvic wands, and this is actually the first pelvic wand in the world that was ever created. It was created by an IC patient, Iliana Brockman. Later, when she wanted to be done, we took it on as a product for ourselves.

It's something we've always believed in because it's made of a borosilicate glass; it's got a special type of S curve with a bulbous head that really allows you to get into the muscles, either vaginally, or we have a longer one for anal use or for pregnant women. It can also be used externally as well. We provide a whole series of exercises in the book. We also provide different types of vaginal lubricants. The anal biome and the vaginal biome are completely different, and the vaginal lubricant should never be used in the anal cavity. We create these products and provide education; we have 1 of only 2 FDA-cleared medical devices in the world that are actually iso-osmolar—meant to go into the vaginal biome, because the vaginal osmolality is 290. The World Health Organization set a level in2016 that you only want to be plus or minus 80 points in your sexual lubricants because they were looking at third-world country sex workers at that point, and they were trying to determine what the optimal osmolality was. Right now, ours is 308, to give you an idea for our aloe glide for vaginal osmolality, and like I said, there are only 2 products in the entire world that are iso-osmolar.

What are the key takeaways for the practicing urologist regarding aloe vera and interstitial cystitis?

Florio: For me, it's safety. Just know that this isn't just any aloe vera. This isn't something that you can go get from any health food store. We have over 30 years of safety data, and no adverse events in over 30 years. Other than a die-off reaction that can happen in the beginning, because most patients with interstitial cystitis are nutrient deficient and this is a high-nutrient content, we have no documented [adverse events] beyond that. From a safety profile, this is something that is safe and is a great option to start out with for patients with interstitial cystitis with no [adverse events]. It's a safe choice to start off with to give them options before you get into the more invasive options. It's a great first-line starting option, and we have a high efficacy rate.

Walker: If I'm looking at a therapeutic, as a clinician, there are several things I'd like to know—safety, of course. The safety profile has been pretty well established. The efficacy profile is a different matter. That's a major reason we're doing this. What I want to know from a therapeutic is, who does it help? How much does it help? How does it help? And then for how long does it help?

Hydrodistension is pretty common in our practice here. You fill the bladder with water and hold it for 5 minutes under pressure and then release it. And that's the therapeutic; it stretches it to as big as the balloon can get and holds it there for 5 minutes and then lets it out. It's done under anesthesia, because these patients have a lot of pelvic pain, and for some, especially with those with a smaller bladder capacity, it's painful while it's being done, but after the anesthesia wears off and all that, apparently provides it benefit. Depending on who you are, the benefit might last 6 months, it might last a year, it might only last a few weeks, or you might not get much benefit at all. A lot of people get repeat hydrodistension, so it does provide some benefit. But the benefit is transient, as a lot of therapeutics are, so you have to continue to do it. How often you have to continue to do it depends on the individual.

And that comes back to, how does it work? What is it actually doing—what's the mechanism? Heather and I have talked about this some, and what would really be cool is to do some mechanistic studies on if aloe vera is helping patients, why is it helping? What is it doing? We have some ideas, but they need to be tested.

You don't have to know why. If you get efficacy and you can measure that and you can compare it to standards, you can say “this helps." That's good enough for most people. What we'd like to know scientifically is why it's helping. Because what that might allow you to do then is to target a mechanism rather than just throw the kitchen sink at things. Anyway, in a nutshell, I want to know, how helpful is it? Who does it help? How long does the help last? That's sort of what we're getting at here. This will not be testimonial based anymore; it will be placebo-controlled blinded study based, and that carries a little bit more weight. The outcome might be exactly the same. From a clinician standpoint, there are a lot of nutraceuticals that can be purchased over the counter. It's kind of a nebulous area. As a clinician you're like, which ones should I recommend, and why? I think this is going to put a little teeth in it when you say this purified aloe vera is a good product to try when you're still doing non-invasive sorts of therapies. This would be a good thing to try. As Heather said, clinicians are already doing that and have been doing it for years. But this will add a little bit of validity and maybe make some clinicians more comfortable now because they can see it's been validated in a controlled study, rather than just patient testimonials.

Florio: We had our initial study, which was double-blind, placebo controlled, but that was in 1995. It was a small subset. This is definitely going to be much larger. We've been working from that 1995 data, and this is our chance to really take this a step further, to be able to take the efficacy further and to hopefully be able to understand that mechanism. We know that aloe vera has over 200 nutrients, 75 of them active, and we know that it's high in glycosaminoglycans. We know that it has d-mannose. We've got a couple of different things going on here, plus all the other nutrients, the other anti-inflammatories and the analgesic properties that are naturally in there. So if we're able to do this, and watch how it interacts with the urothelial cell layer in the future, that would be amazing, because we have always theorized that the glycosaminoglycans create that protective coating in the bladder. We theorized that that mechanism of action underneath is going to be the anti-inflammatories and analgesics and allowing things to pass through the bladder without irritating that lining further. These have all been theories and conjecture that we hope to solidify with this research.