DTPA Chelation Therapy with Ancillary Treatment. Evaluation of Results. May 2021.

There are two elements to treatment for GDD (and actually all of the heavy metal Deposition Diseases) 1. remove the heavy metal, and 2. control the immune response of the host.

Background. Choice of Chelator

This critical point: the chelator used must have a high stability for the metal chelated. The stability constant should be known between chelator and the metals that are being chelated.

To illustrate: EDTA has a stability of 17 (10 to the power of 17) and DTPA has a stability of 22.46 with Gd. This means that DTPA is 300,000 times more stable with Gd than EDTA (yes I have those zeroes correct). This means that it can hold onto Gd much, much better than EDTA, and therefore redistribution is very minimal with DTPA and relatively prominent with EDTA - I estimate perhaps 1% redistribution with DTPA and 30% with EDTA. This does not mean that EDTA cannot pull a lot of Gd out of tissues, as urine Gd results show high urine Gd even with EDTA (and DMSA as well). So stability refers to hanging on to the metal, and does not mean ability to mine the metal out of tissue. The stability of Gd with DMSA and DMPS has not as yet been determined.. I am trying to obtain those numbers.

The best way to think of this is that the stability of the chelator of Gd out of tissues is exactly as important and same concept as stability of the GBCAs themselves. High stability GBCAs (thermodynamic stability): Dotarem, Prohance, Multihance, are preferred over lower stability agents: Omniscan and Optimark. In fact because of the stability issue, the European Medicine Agencies have banned the use of Omniscan and Optimark (and Magnevist) because of lower stability... But these agents are still much more stable than Gd-EDTA.

The importance of stability when considering a chelator to remove Gd (or other heavy metal) is of equal importance as stability is for an administered GBCA, if the stability of a chelator is unknown: it is like administering to a patient a GBCA for MRI study, and telling them this: "I will now inject you with Gd-XYTA. We have no idea how stable it is, but here we go" It would be unethical, perhaps criminal to do this with an MR contrast agent - the same is true with chelators to remove them.

So I hope this illustration makes this point clear.: the stability of a chelator with heavy metals deposited in the body is critical.

So DTPA is the most stable chelator available for Gd (HOPO is more stable still). But also important is that overall it is very stable for most other heavy metals. This is critical, as I have mentioned in atleast one earlier blog, because all chelators move all metals - but if they have low stability there will be a lot of redistribution. Everyone has atleast several metals in them: among them, everyone has lead (Pb).

So EDTA, DMSA, and DMPS will chelate Gd, but it is dirty chelation - meaning a lot of redistribution occurs. That is for example, Gd picked up in skin and dropped off in brain.

All chelators remove Gd; and all chelators, including stable ones, will result in re-equilibration (le Chatelier's principle); but only weak chelators will also redistribute significantly. So if a person has deposition disease to a particular metal (GDD is the example we focus on), all chelators will result in Flare from removal (starts early and lasts generally 1 week), and Flare from re-equilibration (starts 4 weeks and plateaus 2-3 months, then drops). Weak chelators will also result in Flare from redistribution (starts early and lasts generally 1 week). So with DTPA there is always two forms of Flare (removal and re-equilibration) and with EDTA always three (removal, redistribution, and re-equilibration).

Everyone with GDD therefore experiences Flare from DTPA, but just removal (early Flare) and re-equilibration (late Flare 4 weeks +).

Two properties effect Flare: the amount Gd removed and the extent of host reaction to remoblizing Gd. If you don't have a Flare reaction, you don't have Deposition Disease, you have Storage Condition. The amount removed generally can be predicted from the number of GBCAs administered and secondarily when they were administered (more Flare when GBCA injection more recent) and also the type (more with linear). The extent of host reaction, in the majority of individuals is based on how soon chelation is performed after GDD initiated. That is one of the important reasons we do not chelate within 3 months (immunologic memory strong early after start of GDD) and also because patients may recover on their own within 3 months with no chelation. In some people with certain severe Tcell dysregulation or severe Multiple Chemical Sensitivity Syndrome their Flare may be severe even somewhat regardless of how recent the disease started, but it also compounds the recency issue. Unfortunately, at this point in time it is difficult/ impossible to predict this last category, and can only tell by trying standard chelation, also with full immune dampening, and see what happens.

So with experience, the below are the groups that represent general experience:

1. Individuals with just one GBCA injection, treatment 3 months to 1 year after initiation of GDD, 5 chelations may be sufficient to get to 80% + better.

2. Individuals with more complex circumstances, it appears that 15 Ca/Zn-DTPA chelations seems to be the point where they achieve durable 80% + better. This may suddenly happen right at 15.

3. Very complex stories: 20+ GBCAs and/or extremely sick. Unknown number: probably 20+ chelations, more high potency immune modulation. Improvement is expected but in range 60%-70%.

What is very critical to realize on the path of all groups, including group 1, the Flares will cause zig zag response with variable worsening, and /or varying even new symptoms on the path. Stopping early and permanently, because of Flares means that 80% recovery probably will not occur.

If treatment is stopped too early because of the subject's upset at Flaring, then 80% recovery likely will not result, but an eventual lesser recovery actually still is likely (below). Any properly done Gd removal is helpful. After the plateauing phase of re-equilibration Flare, individuals may begin to feel somewhat better- this is an effect of the DTPA chelation having been done (to remove some of the offending Gd), and late Flare of re-equilibration stabilized, and not a beneficial effect of having stopped chelation. Note that I always use the description of 'properly performed chelation'.

The analogy I have used previously and I repeat it here. Stopping chelation too early is like stopping an antibiotic too early, especially for problem infections like osteomyelitis (bone is an appropriate analogy to GDD, as bone deposition is a major issue with GDD and is a major reason why many chelations need to be done) and TB. Infection is an excellent comparator, because bacteria are also exogenous invading entities, like Gd, but the infectious organism can also replicate. Osteomyelitis generally requires 4-6 weeks of iv antibiotics. If you stop at 1 week you cannot expect to get better. In fact in the infection situation often what happens when stopping early, is that one has created a population of bacteria that are resistant to the antibiotic, they will then replicate, and now the infection is antibiotic resistant and may be devastating or lethal. With TB, the situation also a little more complex, duration of treatment is usually 3 months and double or triple antibiotics are used. If one decides one only wants just one of the antibiotics, and then stops that early as well. The same situation has developed: incomplete treatment and likely now more virulent disease.

How this situation arises with Gd and GDD: a certain number of cycles of removal/ re-equilibration/ removal (this cycle always occurs with chelation) must occur for sufficient Gd to be removed to achieve 80% + recovery, and that the host is able to learn to ignore the Gd that is left. That number of cycles is 5 for simple GDD (usually meaning 1 GBCA injection, and that one often being Multihance, Dotarem, or Prohance) and 15 for most sufferers.

When is chelation enough?

When the patient reports they feel 80% back to themselves- stopping or atleast pausing chelation, but continuing all ancillary treatments (probably ancillary treatment is a lifelong commitment) is appropriate. I use also 24 hr urine results, comparing pre to post- chelation (looking for less than 4 times amount of Gd post- compared to pre-), is a reasonable goal, and absolute post results in the mid yellow territory of a 24 hr urine Gd report (about 3 micrograms Gd per 24 hrs). Clinical improvement trumps urine results however.

Spontaneous recovery and Progression?

This depends on the group one is in (using the above 3 groupings). Also the critical thing is that no additional GBCA has been administered.

Group 1. Up to 1 month after GDD develops, 30% of subjects spontaneously recover. At 3 months, if still quite sick, of that population, no chelation (NC) 1/5 spontaneous recover (over 2 years), 2/5 stay stable, 2/5 get worse.

Group 2. Up to 1 month after GDD develops (if it was the last GBCA administered that caused GDD, 1- 10% spontaneously recover. At 3 months, 1 % spontaneously recover, 2/5 stable, 3/5 (- 1%) get worse.

Group 3. Almost no spontaneous recovery (<.001%). 1/5 stable, 4/5 get worse.

Why are cycles of removal/ re-equilibration/ removal necessary?

Gd is more intensely bound in some reservoirs (bone) than others (skin). So much of the Gd removed during chelation is from the less bound reservoirs (circulating immune cells, skin) and then with time Gd from bone is re-equilibrated back to skin (over 3 weeks +). 3 week repetition rate for chelation sessions is our standard, since that appears to be in the Goldilocks spot, of enough re-equilibration has occurred that a lot of Gd will be removed by new chelation, but not too much time has passed that the patient is severely symptomatic from the re-equilibration process.

Is it Gd removal/ re-equilibration making a person sick/Flare or is it the chelator DTPA?

I am 99% certain it is the cycling of Flare from Gd movement that is the issue, and the re-igniting with each chelation session of the immunologic memory to react to Gd. DTPA is exceedingly safe as a chelator and that is why it has been used so extensively in medicine (DTPA is the core ligand in Magnevist and in Tc-DTPA - so a combined total of atleast 120 million exposures to these two alone). There may be unique publications about some issue with safety in very small journals or open access journals. I do not necessarily trust them or rely on them, but I take notice. I would have to see this written in a major journal like Investigative Radiology or JAMA, and a large well controlled series, 1000s of patients for me to believe that there is significant safety concerns with DTPA on its own (since the data base is 120 million + doses showing that DTPA is safe). As with the safety of GBCAs themselves, I am open to changing my opinion, that is why I assign a 1% possibility that DTPA itself could be an issue. If there is an issue with DTPA, it is likely much more severe with all the weaker chelators. There is a small possibility therefore of an immunological reaction to the ligand... but the reality is there is simply no other reasonable choice than chelation with DTPA to get individuals better at the present time. My record: the most published author on the value of GBCAs, to currently the author first describing GDD and developing the most effective treatment. This alone should make it clear - I am absolutely paying attention to everything safety-wise, regardless of what I have written before (which happens also to be correct science, except for not recognizing GDD till 2016) and to create the best treatment even for the extremely rare variant individuals having the rare disease of GDD. For nuanced complex issues that on the surface I find difficult to believe, I would need to see a randomized controlled study, and not the anecdotal experience of one individual.

What happens if Chelation stopped earlier than the 5/15 rule due to Finances/ fear of bad Flare/ Family, etc.?

What is clear is the only real mistake is getting an additional GBCA injection after GDD has developed... always GDD gets worse. Stopping chelation short, the Gd removal Flare occurs early, then followed by the re-equilibration Flare starting in earnest around 4 weeks, and peaking at 2-4 months, but then lessens some, in many (not all). There is always benefit to reducing the body's burden of Gd, so if chelation is stopped earlier than my recommendation, there will have been benefit because the Gd burden has been reduced. Early stoppage, there still is a good likelihood of 60-70% improvement, if healthy ancillary strategy is employed. It is doubtful that improvement will get to 80% + though. It may also be tempting to think that the chelation was responsible for illness and the stoppage has been a good thing. Properly done chelation, as I describe it, always is the right thing, but adjustment to lower chelation agent amount, as described in this blog, may be beneficial on the basis of tolerability for a subject. If severe Flare is the cause of stoppage of properly performed chelation, it is most likely that the subject is in the category that GDD will progress aggressively on its own (which occurs in atleast 2/5 of subjects who have not received any treatment), so it is impossible to know if aggressive natural progression of disease or Flare from chelation is an issue for the subject. I believe the more important contribution is natural aggressive worsening of GDD. I would need to see a controlled series of atleast 100 subjects to be convinced otherwise. Stopping conventional Ca-/Zn-DTPA regimen for 2-3 months or more, and then starting up with a more tolerable protocol (1/2 dose Zn-DTPA) probably has not resulted in any permanent harm.

Expectations during treatment

The path to get to these 5 sessions and 15 sessions end points can be grueling,. It is critical for the patient to realize this. Quite often early on (even after 1 chelation) many get dramatic improvement of one or other symptom - brain fog, vision, etc., and some symptoms may worsen (eg: bone pain),. in others the vision may get worse and not improve finally till the 5 or 15 chelation end points. Durability of the improvements requires repetitive cycles of removal/re-equilibration/removal.

One common symptom that occurs during the journey is cardiac arrhythmia. The only way to improve this is... more chelation, because it is Gd that is the problem. I have heard of patients getting many investigations for this, all of these investigations that I have learned of, have neither been informative nor helped (there is always the prospect of further investigation/ solitary symptom treatment, making the situation worse/ much worse)... The treatment is more chelation to get to the 5 or 15 end point. High blood pressure must be treated, and Clonidine presently seems like a good choice. For pre-existent serious disease, continued treatment is essential, eg: diabetes and insulin.

Regarding the individuals with severe T-cell dysregulation/ Multiple Chemical Sensitivity Syndrome/ early chelation. If Flares too strong for them to tolerate, even with using full strength oral and iv immune dampening, resort to decreasing the amount of chelation agent for each chelation session.

Why have I not done this from the start? Primarily because people have traveled a great distance to get here, and most have limited resources, so with no reason to use less chelation agent: which always means less removal, we have focused on maintaining the amount of Gd removed, and increase the immune dampening . In this above described challenging category though it may still be necessary to reduce amount of chelator. But to date there has been no way to know this in advance, until actually performing full chelation and see how they do. Some patients may prefer Ca-DTPA only as one day chelation (to get more Gd out). For most, using Zn-DTPA only may be a better strategy. So one day Zn-DTPA. In very severe cases of Flaring, 1/2 dose Zn-DTPA is the strategy we employ. The reason we have taken time to get to the 1/2 dose Zn-DTPA regimen is patients pay for the full volume of chelator, and the chelator is expensive, so most prefer to get the full dose Zn-DTPA to get the full value for their money.

This is our approach, and success rate is very high, but not 100% (primarily because of drop-out of severe Multiple Chemical Sensitivity patients from the journey to 5 or 15). The results may well be near 100% if there was no drop out. Nothing though is 100%, and subjects with GDD may have extremely complex genetics and immune system dysfunction. GDD subjects have to understand this - nothing is 100%, and most often one has to try conventional therapy and see the results before going to more reduced therapy. The other cause of lower success is not having used maximal immune dampening, when it is necessary during chelation; we experienced this in the early phase of developing the treatment regimen. Will there be better treatment options in the future? almost certainly yes, but we live in the present.

So: full dose Ca-/Zn-DTPA with oral immune dampening in everyone, and additional iv immune dampening in some where the likelihood of severe Flare is high.

Flare still too severe:

drop to full dose Zn-DTPA only, 1 day chelation. Weekly chelation is a more realistic and beneficial approach when using the one day Zn-DTPA only regimen, as native metals are not disturbed with Zn-DTPA (unlike with Ca-DTPA)..

Flare very severe:

drop to 1/2 dose Zn-DTPA, and unfortunately throw away half of what they paid for (unless you have paired patients on the same day for chelation who require the same level of chelation).

Still use full oral and iv immune dampening.

Can also try to increase chelation amount with time - going from 1/2 dose Zn-DTPA to full dose Zn-DTPA, based on patient increased tolerance with time (often occurs).

I have written before: the equivalent to 1 Ca/Zn-DTPA chelation is 3 Zn-DTPAs, or 6 1/2 dose Zn-DTPA. So 15 chelation sessions of Ca/Zn-DTPA is 45 for full dose Zn-DTPA, and 90 1/2 dose Zn-DTPAs. So 1/2 dose may be impractical if the individual is not local.

The only ancillary treatment described in this blog is concurrent steroid/antihistamines. As I have written in other blogs other ancillary treatments are crucial to add to this regimen. A lot of work is ongoing on this subject. by many individuals. These are written and updated in other blogs and other sites. GadTTRAC will be the site I focus on for ancillary recommended treatments.

It is crucial to understand the essential treatment is removal of Gd, and DTPA is the best we have available. But follow the guidelines above... one may have to resort to using 1/2 dose Zn-DTPA. If the patient is to get better, then a fair amount of what has made them sick (Gd) has to be removed. There is no option. The more Gd removed in a session, the more Flare (but it is a 'good' pain most often- tells you treatment is working). Approaches that are effective (DTPA) chelation, by the nature of the disease and the nature of treatment (removal) always cause Flare, always. Other treatments that do not cause Flare essentially mean that they are not removing much Gd (unless very effective immune suppression is used concurrently). Effective removal of Gd therefore always means there is Flare, and always means that multiple chelations have to be performed.

Richard Semelka, MD