Now to try to move ahead to treatment in the last few minutes. Is this an ongoing persistent infection or is this a Post Lyme Disease. That term always made we wonder, how can we call something ‘post’ when we don’t know and it is the same symptoms that we call Lyme Disease to begin with. So, there is a lot of illogic in this area that has been, I think, used to try and tell people that you don’t have Lyme Disease anymore and the fact that we don’t have evidence for persisting infection doesn’t mean that it isn’t there. So we still don’t know. I don’t know and I have strong circumstancial evidence that it is a persisting infection and I will show you that here in just a minute.
But if you look at the bacteria themselves, they are basically sensitive in vitro to many antibiotics: the penicillins, and we know we can use massive doses of penicillins, a safe antibiotic. If you are allergic, the cephalosporins are generally safe alternatives. It is sensitive to the tetracyclines. It’s very sensitive, perhaps most sensitive, to the erythrolites and the macrolide group and I will come back to them in just a minute. The quinalones which are an ever expanding newer group of antibiotics. Some of the earlier ones including Ciproflox, don’t have good activity but some of the newer ones that have just been released eg Amoxyflox. There was one that was taken off the market and this gets a little difficult because now you are getting into a class of drug that may have some longer term adverse effects to it. So I am already prefacing that long- term therapy is what is needed in this disorder and the reasons for it we can speculate but this appears to be the case.
When you look at in-vitro to actual clinical, it has been known for years that betalactams don’t get inside cells very well and there are a couple of animal tissue culture experiments by the Klempner group and by Dr Raoult's Group in Marseilles that showed that fibroblasts or endothelial cells that were infected with Borrelia had no change in their intracellular Borrelia counts when you use Ceftriaxone, when you used Penicillin but they were changed when you used Tetracycline or the Erythromycin group of drugs. That tends to support the idea that this chronic infection may be intracellular.
Again, we don’t have this as definitive proof that it is the case but it makes the most sense. I mean you have to begin to put this puzzle together a piece at a time and we are doing that and not all of the pieces fit very well but, to the extent that it is fitting to some degree, this appears to be an intracellular infection because it responds best to the tetracyclines and the macrolides and I will come to that in just a second. The others I kind of mentioned.
Now, there is an interesting thing here and this raises a big question about what it is that we do with treatment. And it is a little bit of a digression but I think perhaps it is an important one. Metronidazole, Flagyl, as it is called in the United States, has been used in Lyme Disease based on the idea that it might affect the cyst form but when you look at the genome of the Borrelia they do not contain any sequences to metabolise Metronidazole so there is no way the Metronidazole can have a direct effect on the Borrelia. So, how is it that clinically some patients who are on this seem to have a transient response?
I have thought about this for a while and it takes me about 4 or 5 years to figure things out but whether I have figured it out or not but what I think may be happening and here is the analogy: When you have a patient who has cirrhosis of the liver from either alcoholism or from Hepatitis, one of the things that they do is to go into a coma or not necessarily a coma but confusional state and that is thought to be due to the absorption of some metabolic products of the intestinal bacteria.
So what do we do in that case, we give them Neomycin, an antibiotic which just stays in the intestine, and it reduces the amount of the intestinal flora and thereby decreasing the metabolic products which have to be detoxified by the liver and in that case the liver is impaired. Well how do I jump from that to the Lyme patient and Metronidazole and let me put Cholestyramine in the picture too and perhaps any antibiotic, scary as that may be. What if we are, in the Lyme patient, that in the non- Lyme patient the metabolic products don’t make any difference. Not as far as we know. This is our brain, this is our state of confusion, our state of memory.
What if the Lyme patient is sensitised because we know the Lyme patient is sensitised to wherever their focus is they are sensitised to stimuli, they may be de-sensitised too, but what if some of the metabolic products with an intact liver are creating a problem with the sensitivity of the neurons and maybe what we are doing with the Metronidazole or Cholestyramine in the case of binding metabolic products and temporarily making a person feel better. What if some of our antibiotic therapy is reducing some of the other microflora and we are transiently then reducing some other. In other words, what if this is a secondary effect. How do we know that it is a direct effect on it. So that is one of the issues that we have to still sort out. It seems like it is a direct effect in most of the cases but back now to what we found when I first started to do this in the late 80s is that the first few patients had been on doxycycline, they started to get better, they were relapsing. I was old enough that I knew about tetracycline to begin with. I knew enough pharmacology and pharmacokinetics that I started to question well doxycycline has some distinctly different properties from the parent tetracycline molecule. One is, it is highly protein bound in serum which is why you can give it once a day. But also, that may be a liability that means that most of it is bound in the serum and the free drug is much less and even though it might be more lipophilic, there may not be enough of it to get to the tissues to get inside the cells if that what is needed and tetracycline is not highly protein bound, it is absorbed at least as well, and you are getting 1500mg tetracycline versus 200mg or even 300mg Doxycycline, that maybe that was the difference.
I have not done any control studies but it is pretty clear over the years that tetracycline is much more effective than Doxycycline and Minocycline. Even then, you need to use it over several months. You don’t begin to really get the effect unless 4 to 6 months have passed. So what I do, I cycle it every 6 months and once we came up with our findings with the macrolides that I will show you shortly.
Gender also influences outcome. Why is that? There is probably a hormonal influence on the disease and I know in the chronic fatigue literature it is like a 2 to 1 ratio of females to males and in chronic Lyme it is about the same too where females seem to have a higher incidence and perhaps more of a severity. Just to digress, Herpes viruses shuttle into the nucleus of nerve cells on oestrogen receptors. Glial cells and neural cells have progesterone and oestrogen receptors and Herpes simplex and Herpes zoster viruses are also in sensory ganglia and we have an inordinate number of young people with Shingles who have Lyme Disease and my simplistic thinking is that maybe the neuron is challenged by having more than one organism to deal with and the Lyme expresses itself. Again, idle thoughts, if you will, about what might be happening. However, women do have a harder time, both being cured and having a higher fail rate than men in our studies of both tetracyclines.
Now with macrolide treatment. Macrolide is Erythromycin, Arythromycin, Azithromycin, I did not study Dirythromycin and most of our studies were with Clarithromycin. Before 1992, I really only had tetracyclines and the intravenous treatments. It became pretty clear to me that the intravenous treatments were not curative and so despite the protestations of a number of people, of physicians and patients. that we needed longer term intravenous cetriaxone, I was happy to do that, I did that in a number of cases, six months, nine months, worth and I was unimpressed that we got any substantial sustained recovery compared with what we were getting with tetracycline and when people got intolerant of tetracycline I stopped it for two or three days, put them back on it, and when we reached the plateau after four, five or six months we’d stop for a month or two and then re-start it.
And by doing that sequentially, we would get people better and better and it took 2 or 3 years to do that. I tell patients we average 18 months of treatment but if you have been sick for 10 to 20 years, hopefully, it is not year for year, but we need 2 or 3 years to get you as good as we are going to get you. And most people respond. 75% of people, taking all comers, respond to the tetracycline/macrolide treatment. Now the secret, I think, of the macrolide treatment came after I saw an article, again from Dr Raoult's lab, he is one clever guy. He has this Department of Rickettsiology at the University of Marseilles and I was fortunate to visit him a few years ago and I hope to continue some collaborations. He put us on to the idea and he published in-vitro and tissue cultures. He showed that when you added what is called a lysosomotropic agent that de-acidifies, that alkalises, a compartment inside a cell called an endosome, a late endosome, a lysosome or a late endosome which is naturally acidic, a low pH, that allows the doxycycline that he was using in there against a completely different organism, in that case the Q Fever organism, which is related to Erhlichia, the Coxiella burnetii. He found the kill was much enhanced. So a light bulb went off in my head knowing that the macrolides whilst tremendously powerful in-vitro against the Lyme bacteria don’t work in an acid environment. So I knew we had hydroxychloroquine as the most powerful alkalising agent, Plaquenil in the United States as a brand name, and I said let me start using this. There had been a report by somebody and, I apologise he had died, he had used Plaquenil on 2 or 4 patients. I don’t really remember who that was from the West Coast and he said he had got some transient response.
From the Floor:
Oliver? Baltimore
Professor Donta’s response: Yes, Yes
And the first patient I ever tried this on actually was on Plaquenil for so called sero-negative rheumatoid arthritis and she had been on it for two years without going anywhere. Her Western Blot showed specific reactions. I added Clarithromycin to her regime and she started to improve for the first time. So I enlarged and over the years now I have seen a few thousand people that we have done this with. With macrolide usually I use Clarithromycin because I can use 1000 to 1500mgs as apposed to the Azithromycin where I can only use 250/500 mgs. Erythromycin itself is OK too. It is not as well tolerated but in those who don’t have insurance coverage 1500 to 2000mgs a day and you have to use enough of the hydroxychloroquine which is not a big dose 200mgs twice a day, or 400mgs once a day. But what it does is it allows the lysosomes to be alkalised to allow the macrolide antibody to work. Whether that is what is happening or not, I don’t know. I would like to have a tissue culture model where I actually do this.
Question from floor:
?? the in-vitro studies have shown that it is quite good, very good But some people say it doesn’t work very well … but you are saying that to add the Plaquenil makes it work. (Difficult to hear).
Professor Donta:
Yes, and that has been our observations over the years and all of our patients who have been on Clarithromycin or Azithromycin and had a partial response and then we add the hydroxychloroquine and boy do they have what we call a Herxheimer Reaction and they worry it is a reaction against the hydroxychloroquine and I have to hold their hands with this and not to be condescending but there are a lot of these reactions that are so powerful that it is frightening for the patient to go ahead and go through. So what we learned is that with time, and one has to be patient with this and listen to the patient, that you will get improvement. But for how long you have been sick before, you get treated helps to determine the outcome. I am sorry this has got mushed together. If you have been sick for longer than three years your cure rate, and by cure rate I mean you haven’t had any symptoms at all for a year or more, so these are long term studies that we have been doing. 11% versus 28% and the failure rate 18% versus 5%. This is not subject to statistics, this is not a controlled study, these are observational studies but 75% or more of patients will improve and maintain that improvement after they have been on it even if they are partially improved.
How long they have been sick also determines how long it takes to even begin to have symptom improvement not a Herxheimer worsening but improvement. So if you are sick less than a year most people start to begin to improve within a couple of weeks. This is the percentage of people improving after 2 weeks, 3 weeks, 4 weeks. If you are sick for more than 3 years only 26% begin to see a response in 2 weeks. It takes more than 4 weeks to get a 50% plus response rate. So these are observations that we put down that are kind of known to people in practice.
Now what happens to the Western Blot just to kind of finish off on that tone. If you have symptomatic disease, this is from our first tetracycline paper, we found IgM reactivity in 36% of people. IgG alone 6% and the combination 58%. Once we treated them they became asymptomatic. The IgG sero converted if you will and the IgM reactivity went down to 9% and the IgM and IgG is down to 16% , and then no reactivity. I would be surprised if this would be getting 22%. Why would this be the case? Is this so unusual to have IgM reactivity in a chronic disease? I think not. I think that in Hepatitis you can maintain IgM reactivity, it’s like antigen antibody excess imbalance and I think that IgM can be a marker of chronic active disease and doesn’t have to be just a marker of early disease.
Well my time has gone on but let me say a word or two, sorry about that, but I never wanted to get involved in the supplemental issues but I have observed several things that I think made me get involved in this so I merely get into this because I think there have been well intentioned advice about you need to take this, you need to take that, don’t do this, don’t do that and I think that kind of advice can be counter-productive to a field like this that is a fledgling field that some other physicians think we are dealing with quackery here. And so if we are dealing with other things that aren’t based on strong science, we need to be very careful. I am all for trying to improve yourself. I’m all for cognitive behavioural therapy, exercise therapy, if that helps but I am not sure if that helps much. I am not sure symptomatic treatment by itself by taking the Neurontin or Elovil for sleep. All of these things are important but they won’t cure the disease.
What about vitamin supplements? Neurologists have used vitamins for years. What we noted in the beginning was that some patients weren’t getting better whilst others were and they seemed to be about the same type of patient and that one group of patients seemed to be having the supplements and the other ones not. Around that same time, information came out from the genome of the Borrelia Burgdorferi that no sequences synthesized their own vitamins and almost all bacteria have to synthesize their own vitamins. And, it began to occur to me, are they stealing the vitamins? And the third factor was if you look at chronic infectious diseases, what the body tries to do is to starve the invader to death. It withholds iron, so people get the aenemia of chronic disease, it tries to withhold metals, it tries to withhold various things.
I don’t know if it withholds vitamins I don’t have that answer but if you measure a person’s blood it will be a rare person who doesn’t have normal B1, B2, B6 levels. So I ask patients to humour me and not take any supplemental B or C vitamins. The reason for C is that it counteracts the effects of the hydroxychloroquine. It is a strong acidifying agent. So I tell them to go about your business. Eat or drink whatever you want but don’t be doing any special supplementation until we are done. It appears we are getting better on that. How am I going to measure that I can’t measure that so I am reluctant to even talk about it.
And what do we do about hypobaric oxygen? The patients who have done it say they transiently get better and they have up and downs but it doesn’t appear to be curative.
Heat therapy – I don’t think we can fry this organism. I don’t think we can heat up the body enough to get rid of it.
I welcome other approaches to try and help this disease but these are the issues. Future directions – we need to identify Lyme specific products, we need controlled clinical treatment trials and God only knows how many times I have tried to get support for this. But we are talking about several million dollars basically, this is not a $30,000 project. And we need vaccines eventually that can work.
Apologies for taking this amount of time and thank you for listening.
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