Oxidative Stress in Chronic Liver Disease:
The Role of Glutathione.

Theodore Hersh, M.D., MACG

Professor of Medicine, Emeritus, Emory University Atlanta, Ga.

Glutathione, a tripeptide composed of glutamate, cysteine and glycine, is present in most plants and animal tissues and is the most important and ubiquitous low molecular weight thiol compound.  Working intra and extra-cellularly in its reduced form, L-glutathione, abbreviated as "GSH", is the body's key antioxidant and protectant.  GSH has multiple functions in disease prevention and in detoxification of chemicals and drugs while its depletion is associated with increased risks of toxicity and disease. GSH works synergistically with the other cellular antioxidants to neutralize and scavenge oxygen and other free radical species and thereby prevent or diminish "oxidative stress".

A deficiency of hepatic GSH and its antioxidant partners and/or an increase in toxic free radical species may contribute to the progression of liver disease.  Thus, is there a role for glutathione in the management of patients with alcoholic liver disease and viral hepatitis, particularity those with Hepatitis C?

There are only a few studies in the medical literature which relate to the role of antioxidants, particularly L-glutathione, in chronic liver diseases.  In 1996,   Barbaro and colleagues from Italy, reported on the levels of glutathione in liver, blood and lymphocytes of patients with chronic hepatitis C.  Some of these patients were also HIV positive.  The liver is the most important source of GSH levels in blood, but dietary GSH also raises tissue levels.  GSH content in these three sites was significantly reduced in patients with hepatitis C and correlated with the severity of their liver disease as well as with the ability of the hepatitis C virus to replicate. The GSH levels in those cases that also were HIV positive were even more significantly lower than those with hepatitis C who were HIV negative.  The lowest GSH levels were more evident in those patients addicted to drugs. Because of these low GSH levels, both diseases are more resistant to anti-viral therapy, interferon for those with chronic hepatitis and antiretroviral drugs for those with HIV.  Beloqui's studies in Pamplona, Spain suggest too that repletion of glutathione levels improve the response to interferon treatment in these cases with hepatitis.

DeMaria and co-investigators at the Oklahoma Medical Research Foundation also confirmed that oxidative stress occurs in patients with chronic hepatitis and showed that the levels of free radicals correlated with the activity of the hepatitis.  In another study Dentico and colleagues, also in Italy, repleted glutathione levels with high intravenous doses in patients with fatty livers (steatosis) secondary to alcoholic hepatitis or viral hepatitis (B or C).  They recorded marked improvement in patients' liver tests, lasting even several months after GSH treatment. Charles Lieber at Mt. Sinai in New York also showed the presence of free radicals due to oxidation of lipids in patients with alcoholic liver disease while Fitzgerald and co-workers in Philadelphia concluded that oxidant stress contributes to the deterioration of the liver disease.

What are the conclusions in Mid-1998?  The evidence is clear that oxygen and other toxic free radical species resulting from oxidative stress occur in chronic liver disease and contribute to liver damage in various common types of chronic hepatitis.  Blood and liver antioxidant levels, particularly those of L-glutathione, are found to be reduced in these patients compared to age matched controls.  Thirdly, repletion of L-glutathione appears to improve liver cell damage as reflected by standard liver tests.  In chronic hepatitis C repletion of glutathione not only impairs Virus C replication but also renders interferon anti-viral therapy more efficacious.

Dr. Bonkovsky at the University of Massachusetts has elegantly reviewed the therapeutic options in chronic hepatitis C. He concludes that these preliminary studies are most exciting and worthy of further rigorous clinical evaluations, stating "the future of therapy of chronic hepatitis C will likely include measures to decrease oxidative stress and injury, and the use of multidrug combinations, including inhibitors of hepatitis C virus." However, every patient with chronic liver disease should consult with their physician for all therapeutic options in the management of their condition.

Biologically Active Whey Protein Supplementation as an Immune System Booster

Undenatured whey protein is now recognized to be the most effective way to raise the intracellular levels of Glutathione (GSH), the body's own master antioxidant and detoxifier.

Research has confirmed the crucial role of optimal Glutathione levels in the prevention and recovery in numerous diseases.

Undenatured whey protein concentrate contains exceptional amounts of cysteine, glutamine and active peptides, which are principle players in the coordinated T-cell response of macrophages and lymphocytes.

Research is continuing to discover that undenatured whey proteins contain many of the immune building constituents inherent in mother's milk. The list includes:

Lactoferrin, iron modulating anti-viral and anti-bacterial properties.

Immunoglobulins (IgG), numerous immune system benefits.

Active Peptides (specialized paired amino acids), exhibit a beneficial information transfer factor effect on the immune system as well as boosting intracellular Glutathione.

Undenatured whey protein has been clinically shown to help improve the health status of persons with CFIDS, AIDS/HIV, Toxic Heavy Metal Burden, Liver Dysfunction, Cancer, Cystic Fibrosis and Hepatitis C.

Jeffrey Peterson et al writing in the Proc Nat’l Acad Sci states:

“We show that in all cases, Glutathione (GSH) depletion inhibits Th-1 associated cytokines production and/or favors Th2 associated responses. Further, by charting the responses of isolated cell populations mixed in vitro, we demonstrate clearly that the decrease in Th1 cytokine production is due to the short-term, readily reversible depletion of APC GSH.”

Note: APC stands for “Antigen Presenting Cells.” The experiments showing that glutathione depletion favors Th2 immune responses was done in mice. When glutathione levels were returned to normal, Th1 responses were favored. (1). Persons with cancer, HIV infection, HHV-6 (CFIDS), candidiasis and chronic insomnia always have a predominance of TH-2 cytokines (i.e. IL-4, IL-6) and a shortage of TH-1 cytokines (IL-12, IL-2 and IFN-gamma).

1. Proc Natl Acad. Sci; March, 1998 published in Immunology magazine

October 24, 2000

I am a 41 year old white female that was diagnosed HIV+ in 1986. To date I have been asymptomatic. I started taking protease inhibitors and anti-virals in 1995. My T-cells have not been over 200 in the past 9 years. In July of this year my viral load was 800+ and my T-cells were 160. My boyfriend did some research on the immune system for me and that's when he found your product, ImmunePro Rx. At that time I made a decision to stop taking all of my HIV meds and try another approach. I began taking ImmunePro Rx faithfully,

5 grams, 3 times a day. Three months later I had my blood work done. My viral load was 600 and my T-cells were 252. I attribute the improvement in my lab work solely to ImmunePro Rx. Especially considering I have been off my meds for 3 months and not only did my T-cells improve but my viral activity decreased. To me, that says a lot for your product. I intend to continue with this protocol and look forward to seeing my next lab results. Thank you ImmunePro.

Patti.L. Tampa, FL

What follows is a testimonial that I have volunteered to write because I am obtaining so much benefit from ImmunePro Rx.

Wellsprings
To Whom It May Concern,

I am a 36 year old woman who has had Chronic Fatigue Immune Dysfunction Syndrome (C.F.I.D.S.), also known as Myalgic Encephalomyelitis (M.E.), since I woke up with what felt like the "flu" on August 1, 1989. I had to drop out of a Ph.D. program in which I was enrolled, and give up my full-time job. In the ensuing eleven years, I have tried innumerable therapies in an effort to regain my health, spending literally tens of thousands of dollars. At this time, I am completely unable to hold even a part-time job, to raise a family, or indeed to do very much at all besides the most basic of activities (showering, a little grocery shopping, etc.), and these must be carefully spaced throughout the week (i.e., shower one day, go to the store another day, etc.)

Although I have only been taking ImmunePro for about a month now, I can already state with confidence that it is the single greatest therapy, prescription or non-prescription, that I have tried. I had been taking a whey protein isolate (as opposed to a whey protein concentrate, which ImmunePro is), and had been thrilled with the results that I was achieving with it. I was actually hesitant to try ImmunePro Rx, because I was so happy with the other product I hesitated to stop using it.

I am immensely pleased with my decision to use ImmunePro Rx . I started with a very tiny amount (slightly less than one gram) and immediately felt slightly more energy and more "normal" than I had with taking twenty grams (two packets) of the whey protein isolate. I have slowly increased the amount of ImmunePro Rx that I am taking, so that I am now taking approximately three grams. The more I take, the better I feel, so I am extremely excited and optimistic about the effects that ten or twenty grams may have.

Because I feel that several heterogeneous but similar illness are currently being classified as C.F.I.D.S., I feel it important to detail exactly what my symptoms are and therefore what the ImmunePro Rx is ameliorating. Basically, much of the time I feel like I have the flu. I have low grade fevers, swollen, painful lymph nodes, chills and general body aches. Of course I also have devastating fatigue, extremely limited stamina and both delayed sleep phasic disorder (phase-shifted sleep) and insomnia.

ImmunePro Rx has increased the amount of activity I can tolerate before having flu-like symptoms, increased my energy overall, improved the sleep disorders (and this is truly amazing, as even though I routinely take a fistful of supplements to sleep, nothing has made the difference that ImmunePro has), and given me brief windows of time where I feel what I can only describe as "normal". During these "normal" periods, I not only do not feel sick, I actually feel good!

I am enormously grateful for the existence of ImmunePro Rx, which promises to give me back my life.

Very Sincerely Yours,

Stephanie F.

San Francisco, CA

Here is my whey status report:

I had been taking Immunocal for 6 months with some improvement at 1-2 packets a day. I decided to try ImmunePro Rx because of the lower price and have been on it for for 3 weeks. I started out at 2/3 a scoop 2x's a day. I immediately felt like it is doing something powerful - a feeling that I did not get with Immunocal. I have worked up to almost 2 scoops per day (1 scoop in the AM and the other in afternoon). I have some days where I am feeling a little more tired, but overall I am feeling really great and have had increased energy. I have been exercising a bit more with no major setbacks. This does seem to be a more potent product. Thanks to all who are sharing their reports on the whey - I am very excited about these products!

Stephanie O.

Wellsprings

I want to thank you for all the information you sent concerning whey protein and Immunepro Rx.

The patients that I have put on Immunepro Rx have been using it to enhance athletic performance for the most part. They have seen great gains in muscle development, speed and performance with absolutely no side effects. We have tested the product using before and after symptom questionnaires with very marked improvement in all types of symptamatology. We have also noticed a number of people that have remarked their eyesight has improved in as little as two weeks.

My two sons use the product on a regular basis and between them they have qualified for numerous national championships in 5 different sports.

I would like to set up further testing of the product using the ACG and symptom surveys, I am sure the results will be most favorable.

We recommend to our athletes that they take it within 15 to 20 minutes after exercise to get in that window of recovery and have them take magnesium lactate to facilitate transport.

Joseph J. Teff D.C.

Previously provided Chiropractic services for:

• Team Hayes International Cycling Team

• Trek Factory sponsored state cycling team

• University of Wisconsin Football team and coaches

Current Projects:

Consultant to Biotonix Corporation which designs computer software programs for biomechanical analysis.

Undenatured Whey: Detox and Antimicrobial / Antiviral Benefits
(Written by Carol Sieverling, based on a letter from Dr. Cheney and a lecture transcript.)

In January, Dr. Paul Cheney informed those scheduled to participate in his study of undenatured whey that he was switching to a new, more powerful product: ImmunePro Rx. Based on sophisticated biochemical analysis, it is believed to be two to three times more powerful than the other two whey products currently used by his patients, Immunocal and ImuPlus. It also happens to be less expensive!

Why all the excitement about undenatured whey? Dr. Cheney's original study with Immunocal showed that it had the ability to restore intracellular glutathione levels, something that neither glutathione supplementation nor injections have been able to accomplish to any significant degree. Virtually all CFS patients have low levels of glutathione. Even if glutathione levels are at the low end of the normal range, other markers (elevated lipid peroxides, elevated citrate, depressed alpha ketogluterate) usually indicate problems with its functionality. Dr. Cheney believes that this deficiency is the key problem in CFS patients, especially over time.

Glutathione has many important functions, two of them critical for CFS patients. First of all, it is a major player in our detoxification pathways. Glutathione deficiency impairs the body's ability to get rid of toxins, whether they are environmental or the by-products of cellular metabolism. We slowly become toxic, storing away poisons in our fatty tissues, muscles, organs, and brain. This cellular detox failure can make us canaries to our environment. Good detox programs that have worked well on people with other illnesses can actually put some CFS patients in the hospital. Therefore the glutathione deficiency needs to be addressed before any serious attempt is made at detoxification. Immunocal, ImuPlus and now ImmunePro Rx appear to restore normal levels of intracellular glutathione in most patients, allowing the body to detoxify. (If the dose is too high it is possible to mobilize more toxins than the body can handle, resulting in a "crash". Reducing the dose eliminates this problem.)

Secondly, glutathione is a powerful antiviral / antimicrobial mechanism. A glutathione deficiency compromises our ability to keep old viruses dormant and fight off bacteria. This is why so many of us test positive for EBV, CMV, HHV6, Mycoplasma, and Chlamydia Pneumoniae, etc. These pathogens are likely not the cause of our illness, but simply opportunistic infections. Indications are that undenatured whey can stop the replication of any intracellular microbe, including HHV6, Chlamydia Pneumoniae, and Mycoplasma. Treating them can greatly reduce symptoms and improve well being, and in some cases lead to recovery.

Patients who tested positive for Chlamydia Pneumoniae and Mycoplasma before the original study tested negative at its conclusion six months later. One packet a of Immunocal, the original patented undenatured whey, was sufficient for the C. Pneunoniae. Regarding HHV6, only those on two packets a day of Immunocal tested negative after treatment.

The traditional treatment for Mycoplasma and Chlamydia Pneumoniae is 18 months of triple antibiotics, which can wipe out a patient's gut flora and leave them a gut ecology cripple for the rest of their lives. This treatment approach is much gentler and appears to be just as effective. Dr. Cheney recommends starting with one teaspoon twice a day, increasing to two teaspoons the second day, etc. In the current study half the patients are taking four scoops a day (a total of 20 grams, or 4 tablespoons), and the other half are taking eight scoops a day. Some patients may need to start with much smaller doses and slowly work up. Dr. Cheney recommends split doses in distilled water on an empty stomach. For those familiar with Immunocal or ImuPlus 10 gram packets, one scoop of ImmunePro Rx is 5 grams, though ImmunePro Rx has two to three times the bioactivity.

* Dr. Paul Cheney is currently using ImmunePro Rx™ with the patients in his clinic.

February 1999: (Transcription)

. . . immune-activation states can also induce the activation of endogenous microbes in the presence of Glutathione deficiency. And that might explain why in this immune-activation state that we call Chronic Fatigue Syndrome you see a lot of endogenous viral activation such as EBV, CMV, HHV6, mycoplasma incognitus, chlamydia pneumonia, candida, and on and on and on. You see the activation of this microbial ecology, and why is this happening? It could be that it happens because cytokines in excess stimulate these organisms, especially in the presence of glutathione deficiency. The converse is true, however. In the presence of good glutathione levels, it's very difficult for that to happen

. . . . Conclusions from all of this are: Glutathione has potent anti-viral properties--if you raise the glutathione level you can stop the replication of most any, at least, intracellular pathogen. Chronic fatigue syndrome patients are glutathione deficient. Glutathione deficiency itself has a potent pro-viral effect. That is, not only does (high?) glutathione levels tend to act as an anti-viral, but glutathione deficiency produces a pro-viral effect. It can actually augment viral replication. Augment it from the case of toxins, toxins could augment viral replication and also cytokines themselves. So immune-activation states would itself augment these things.

. . . I'm trying to set the stage for how important it is to address this glutathione defect. It could be THE major issue in this illness. Maybe not so much in the beginning, but over time become the major issue. Because we're dealing with a sub-group of people who have cellular detox failure and all that that causes. Because if you have cell detox failure, you become a canary to your environment. . . . If you get a glutathione defect, then you become vulnerable to your own cell toxicity, specifically the portal circulation.

We found out that when you give oral reduced glutathione, it helps a little bit in some people, especially these pressure toxic headaches they get. But when you keep raising the dose, they actually get sick again, and it was never a very impressive response. When we tried NAC we saw some evidence of toxicity. In the use of NAC--I'm concerned about high-dose NAC in this disease. I think it may be toxic. We tried other methods to affect glutathione. Nothing seemed to be working.

Then we got wind of undenatured whey protein, lightly denatured to preserve the peptide action of this milk protein. It's concentrated to about 90 percent protein and it's very, very lightly denatured. In fact, the more lightly they denature it, the better the action appears to be. And the more they denature it, the less active it appears to be. In fact, if you denature it completely, down to its constituent amino acids, it really doesn't work well at all. People who normally have milk protein allergy seem to tolerate this, by and large. Not 100 percent, but by and large.

This is the data from a six-month study. There were eight people entered into the study, seven of them completed the study. We got data on seven of them. One dropped out at three months for a reason involved with the design of the study. (Note from Carol: the patient dropped out when the study protocol randomly required half of the participants to drop to one packet (10 grams) a day at the halfway point. He was improving so much on two packets a day that he refused to drop back, so he quit the study.) The first three months of the study we treated with two packets a day, and then the second three months, half were randomized to two packets a day and half were randomized to one packet a day. We wanted to see if you could tell a difference clinically or by other means between one packet a day versus two packets a day.

We did this because there was some indication that the more you treat with this, the higher the dose, the better the effect. When you look at the group that goes from two packs a day to one pack a day, you can see this nice dip where they started going back up (in their urine lipid peroxides). Suggesting that one pack a day doesn't work very well. (He's referring to a slide of a chart here, I think.)

By the way, you can extend this--there are people, I've discovered since the study was done, that do really well on three packs a day and not very well at all on two. (Note from Carol: Cheney told me in October that he has patients on 4, 5, and even 6 packets a day!!!) So clearly there is a dose response issue. Two packs a day would probably be my recommended starting dose, but I wouldn't hesitate to go up if it seemed like it wasn't working.

This is the exciting stuff. We wanted to see not only if this product improved glutathione functionality, which it did, but we also wanted to see if it knocked out micro-organisms, like the PNS article said it would. Chlamydia pneumonia is an intracellular pathogen. It's a common cause of hospital-acquired pneumonia. It ubiquitously infects the population, but seems to activate under certain conditions. And if it activates, some of the clinical conditions of this organism are chronic sinusitis, pharyngitis, and laryngitis. But it also gets into the central nervous system.

In a study published by a neurologist out of Vanderbilt showed that chlyamdia pneumoniae may be a very important pathogen in multiple sclerosis. Indeed, data they shared with me recently (and this is coming to publication soon) showed that 80 percent of the cerebral spinal fluid of MS patients is actively infected with this organism. Versus 15 percent of other neurological diseases that are not MS. In a journal-published article on neurology, aggressive treatment for chlyamdia pneumoniae rapidly reversed an acute exacerbation of multiple sclerosis.

So we measured IgM levels for this pathogen at Vanderbilt. Most laboratory measurements of this organism are not very good, so this is a research grade assessment, and probably may not generalize to the run-of-the-mill types of tests that you might get in your local labs. But IgM elevations of 1 to 1600 (?) dilutions is evident of significant active infection with this organism. Six months later, it just wiped it out. IgM just fell to normal levels. It didn't really matter whether you were taking one pack a day or two packs a day. Just wiped it out. Makes you wonder what this might do for MS. Think about that.

We also looked at mycoplasma fermentans and mycoplasma penetrans. Both of these pathogens have been linked to Gulf War Syndrome. They've been linked to chronic fatigue syndrome. Again, they may be a relatively ubiquitous mycoplasma species, intracellular, and can cause a variety of problems when active. Again, by PCR done in Irvine, California. We were able to show that this product also wiped out mycoplasma incognitus and penetrans.

Then we looked at HHV6. It was a little mixed here. We tested three people.

By the way, this study was designed to do some microbial testing on everybody, but not everything on everybody. The patients were allowed to pick and choose depending on what we had in their chart before. We weren't able to do everything on everybody because they were paying for this.

We did HHV6 rapid culture testing, which is a technique developed by a company in Wisconsin. This particular culture technique uses an intermediate (captures fiberglass?) cell line, so that you are positive only if you are really infected, so it reduces false positives to zero. That is, under these conditions, all normal people are negative. You have to do that because HHV, both A and B strains, are relatively ubiquitous. Under these conditions, we had two positives and one negative at beginning of the study. The person on two packs a day went to zero culture (negative); the person on one pack a day stayed positive. The person that was negative stayed negative. Suggesting that maybe this isn't as good against viruses as it is against bacteria, but at two packs a day it might be good against viruses. Again, the numbers (of participants) are small.

But to me, the satisfaction of this is tremendous because I'm always faced in this disease population--well, are they sick from EBV? or are they sick from HHV6? or are they sick from mycoplasma incognitus? or are they sick from c pneumoniae? And the [traditional] treatment for mycoplasma and c pneumoniae is 18 months of triple drug antibiotic therapy. And if we're wrong on this issue, we've wiped out their gut flora and leave them a gut ecology cripple for the rest of their lives. So now what we have is a nice way to address almost any microorganism that happens to be there. Just as the PNS article suggested.

CFS Radio Program February 28th, 1999 Roger G. Mazlen, M.D. Host With Dr. Paul Cheney, M. D., Ph.D.

Dr. Mazlen: We are really honored today to have a very eminent guest with us today, Dr. Paul Cheney. Dr. Cheney is the founder/director of the Cheney Clinic which is located on Bald Head Island in North Carolina. He's also prominent from the early beginning of research into Chronic Fatigue Syndrome or CFIDS. He's a board certified internist. He additionally trained for two years in tumor immunology at the CDC and then became Chief of Medicine at the Mount Home Airforce Base Hospital in Montana. Of course, from there there's a long history of research and involvement and prominence in the field of research into Chronic Fatigue Syndrome, so I'm going ask Paul to tell us a little bit about how that started. Paul, welcome to the show and we'd like to hear from you now.

Dr. Cheney: Yes, thank you, Roger. My introduction to this illness was as a practicing internist on the north shore of Lake Tahoe in 1985 when in the spring of that year we began to see an increasing, actually, an accelerating number of patients, peaking in the summer of '85 and then decelerating quickly by the fall of '85, producing about 200 cases in that small area of the California/Nevada line and the Sierra Nevada Mountains. Initially we thought there was some sort of flu-like illness among our patients who were previously quite healthy but over time they would not resolve the symptomatology and evolved slowly over time a triad of symptoms, characterized by debilitating fatigue, increasing cognitive disturbances affecting their ability to function cognitively, and then incredible pain, particularly muscle pain but also other kinds of accelerated pain. And that was the triad that we saw and these patients would not get well. And so we invited both the CDC and later Dr. Komaroff, then chief of medicine at Harvard who'd been seeing a large number of cases in Boston to come out and help us research this epidemic culminating in a publication in the Annals of Internal Medicine at about 1991 describing what we saw in that time.

Dr. Mazlen: Well, of course, it's history and most of the patients with Chronic Fatigue Syndrome are well aware of your work and Peterson and others in this area and we commend you for those early efforts, but you've gone a long way since. You've been very much involved nationally in the area of research into Chronic Fatigue Syndrome. You had mentioned to me a new concept as to what the disease is as it develops, when we had spoken prior to the show, maybe you would just like to go into that a little bit.

Dr. Cheney: Yes, the syndrome we call Chronic Fatigue Syndrome probably belongs to a larger subset of disorders known as post-infectious or post-viral syndromes, at least in a hefty subset of patients, perhaps 60-70% who were perfectly healthy until one day they come down a flu-like or mono-like illness and aren't the same thereafter. There's a smaller subset that have more insidious onset and they represent a different type of illness, but the majority of patients appear to be a post-infectious or post-viral syndrome. In that regard, there's another syndrome known as Reye's Syndrome, which evolves typically in children, although it can hit adults as well, who come down with a viral illness, sometimes the flu, sometimes chicken pox, and are resolving the acute viral syndrome and then take a dramatic turn for the worse almost at the moment they're getting better from the viral syndrome and the disease we call Reye's is characterized by disturbed liver function in the aftermath of the viral infection, that then produces a severe toxicity that affects the central nervous system and frequently death ensues. And Chronic Fatigue Syndrome might be viewed as a sort of slowly developing Reye's Syndrome in that they come down with a viral syndrome and then they emerge from that with a disorder in liver function and detoxification at the cellular level, we think involving glutathione but also other pathways, and that results in a progressive toxification systemically, particularly from the portal circulation similar to Reye's and then a hit to the central nervous system, probably a zenobiotic toxicity to the deep brain structures that gives us the emerging picture of debilitating fatigue, cognitive disturbances, hypothalamic-pituitary-adrenal axis disturbances and severe pain. So, it's sort of like a post-infectious slowly developing Reye's Syndrome as an analogy to another more acute illness we call Reye's Syndrome.

Dr. Mazlen: Now, also, there's a connection here which you make me aware of to the 37 kilodalton variant of the RNase L and I want you to do on and talk about that.

Dr. Cheney: Right, well, that's a really intriguing issue because no one really fully understands why liver detoxification fails in Reye's Syndrome, but in Chronic Fatigue Syndrome there was discovered some years ago by Dr. Robert Suhadolnik that a very significant up regulation in an enzymatic pathway known as the 2-5A RNase L pathway was highly activated in Chronic Fatigue Syndrome. This particular pathway, although a potent antiviral pathway inhibiting viral protein synthesis and therefore viral replication, also inhibits human protein synthesis and enzyme production and could easily be the cause of this liver detox and cellular detox failure in this disorder that sets off this compounded set of problems. Dr. Suhadolnik, a few years after discovering this pathway was highly activated then discovered it was aberrantly activated with evidence of a low molecular weight, 37 kDA protein, kDA simply that as kilodalton, the size of the protein. The normal RNase L is 80 kilodaltons. This low molecular weight is only 37, slightly less than half the size. This could particular enzyme is extraordinarily active, over 6 times more active than normal RNase L and it resists proteolytic degradation and therefore lasts longer in the body and it can really cream protein synthesis and enzyme production and cellular function and from that human function.

Dr. Mazlen: Apparently, it also uses up some of the precursors for glutathione production, is that correct?

Dr. Cheney: Well, it certainly is a rapid cycling enzyme system that consumes ATP by the bucket load, kind of a black hole for ATP, as it were. So, it's a consumer of energy, but most importantly, it impairs enzymatic production in virtually every enzyme in the body. It has a huge, huge effect on human function.

Dr. Mazlen: So, this is one of the cornerstones, but on the other hand, it's only been found in about 30-40% of Chronic Fatigue Syndrome cases.

Dr. Cheney: Correct. That was kind of an interesting discovery because we were hopeful that it might be true marker for this disease, but it was not to be present in a large subset, but it was primarily present in the first 5 years of illness and at about 5 years or so, plus or minus, it begins to down regulate, such that by the 8th to 12th year of illness there's virtually no 37 kDA left, yet the patients do not necessarily recover, although we think their illness shifts or changes as this 37 kDa down regulates.

Dr. Mazlen: I want to ask you, Paul, if you can talk a little bit about your current research in Chronic Fatigue Syndrome?

Dr. Cheney: Yes, of course we have a number of projects. One is of course collaborating with Dr. Suhadolnik regarding the 37 kDa protein and it's meaning in this disorder, but a recent effort at this clinic has been--actually it's the culmination of several years of looking at defects in detoxification pathways, in particular the glutathione system which appears to be particularly impaired in this syndrome and we tried treating this in a variety of ways, first, obviously with oral therapy with reduced l-glutathione and injectable glutathione and in a few cases with precursors to glutathione such as n-acetylcysteine and although we were seeing modest benefits, particularly pressure headaches, with reduced l-glutathione, we were not getting a huge clinical benefit overall and the glutathione system remained impaired as measured by endpoint markers such as liver peroxides in the urine. So we began to look out at other approaches that might work better and we became aware of a weakly hydrolyzed whey protein concentrate, marketed as Immunocal™ (he is now using ImmunePro™)but in fact a whey protein concentrate that's weakly hydrolyzed and that appears to be important in it's effectiveness. We read about this product and were interested in its potential for improving the glutathione system and from there wondering if it would help this disease. So, we launched a program about 6 months ago testing the efficacy of this in CFIDS and we are, at this point, analyzing the data and pleasantly surprised at what we're seeing.

Dr. Mazlen: So, you're getting some positive results then?

Dr. Cheney: Yes, we are and we do think, however, there's a subset of patients that appear not to respond to this product. There's a larger subset that appears to respond clinically. Some interesting and unexpected results were seen in the study but overall I think it was a positive clinical response and other interesting facets of this product making us a lot more interested and perhaps more aggressive in treating this glutathione defect with these kinds of products.

Dr. Mazlen: Now, this is a small study so I presume that you feel at this point it warrant expansion into larger trials. I think so.

Dr. Cheney: We only have 7 patients which isn't a large number, but there was a very consistent response in several areas suggesting that 7 is almost enough to make some observations about it, but I think from a scientific standpoint we'll need more studies and larger numbers.

Dr. Mazlen: Well, it's exciting because anything that's helps this population of people who reign from moderate to severely ill or totally disabled is certainly a welcome advent to the therapeutic armamentarium for us, primary care physicians and researchers. I want to take one quick call on the line from Jeeney, then we'll go on with other things. Jeeney, welcome to the show. Do you have a quick question?

Jeeney: My question today is about ampligen. I've been hearing so many mixed reviews. After you had your study and the people stopped taking the ampligen, what was that result?

Dr. Cheney: Well, there are several things I think that are important to note about ampligen. First, of all, there's no doubt in my mind as I've seen it in clinical practice that this drug is bioactive in this syndrome. That is it can help people sometimes substantially. However, it does not help everyone. And it may be that the reason--there may be a couple of different reasons--one reason may be that no everyone has activation of this RNase L pathway which ampligen appears to be very potent at regulating, in CFIDS at least, downregulating. If that pathway is not activated, then ampligen may not be very rational or even effective. Ampligen also has potent antiviral properties as well and I think some of these patients may not have a significant viral activation state which may be another reason why it doesn't work in everyone. The other parallel issue for ampligen is that it appears that the longer that you take it, if you are responding to it, the better the outcome and in the initial study in 1991-92 we essentially only treated for 6 months in most cases, a year at most and that may have been a relative under treatment and so when you're under treated with ampligen, even if you're a responder you tend to degrade very quickly when you stop and conversely, when the drug is treated for longer periods of time a better clinical therapeutic plateau is reached, there appears to be some stability at maintaining a plateau once the drug is stopped. So, I think it's kind of uncertain in my own mind exactly what will happen when you stop this drug. My sense is that if it's stopped prematurely, one will end up pretty much back where you were. If it's maintained over a longer period of time, there's a much better chance of stability. If you are a responder, the chances of a response, all comers, appears to be 2 chances in 3 and that might be raised a little bit if one targets a subset of patients, specifically ones that are within the first 5 years of their illness who have abrupt onset and who may have activation of this RNase L pathway.

Dr. Mazlen: You mentioned earlier, briefly to me, not on the show, but privately, that there's a significant incidence of chlamydia pneumoniae found in CFIDS patients. Can you comment further on that?

Dr. Cheney: Yes, of course this syndrome has sort of a long history of viral and, more recently, non-viral microbial activation reported as associated with this disorder. For the listening audience, it's important to distinguish between association of an organism versus causality, and that's a thing critically important in this syndrome. This syndrome may represent an immune activation state and with the disordered glutathione system which can create a sort of biological terrain in which microorganisms that lay dormant in our bodies almost back from childhood can activate and then other organisms that we may catch during our lives, and these organisms are not typically active, but are kept in a dormant state by our immune systems indicates that in CFS the conditions are ripe at times for the reactivation of these dormant and latent organisms. One of these organisms which is ubiquitous in the population but typically not active is chlamydia pneumoniae, which has been reported as active in a large percentage of these cases.

Dr. Mazlen: Well, that's a significant addition because they still have trouble with a lot of infectious disease specialists in dealing with Chronic Fatigue Syndrome. Many of them don't feel it has anything significant if they just show a positive Epstein Barr viral capsid antibody, IgG, etc. I want you, Paul, to give me your email address for the audience.

Dr. Cheney: Yes, the email address is pcheney@fnmedcenter.com, we have a website which is www.fnmedcenter.com. We have a caller on the line, let's go to Caroline. Caroline, do you have a question?

Caroline: I actually have two. One is that College Pharmacy is selling a generic Immunocal and I wanted to know whether Dr. Cheney thinks that is as good or if he's familiar with it and the second is that if you have the test for the RNase L marker for ampligen and you don't have that activated pathway, are you definitely not a good candidate for ampligen?

Dr. Cheney: Very good questions. Regarding generic type products of a whey protein concentrate, we do know from the patent application involving Immunocal™ that in comparison with the typical whey protein concentrates, the Immunocal™ product is far superior in it's ability to improve glutathione status. With regard to other generic products that might be available however, I can't comment. I haven't looked at them. Theoretically, in my view it would be possible to make a generic that would work, I just don't know if a particular generic will work and that would have to be looked at carefully. With regard to RNase L itself, if it's not activated doesn't exclude, in my opinion, a response to ampligen, but rather reduces the chance somewhat, I don't know how much, but I think there are people that definitely responded to ampligen to did not have activation of this pathway because ampligen may do more than just modulate this enzyme pathway. It has other effects.