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Multimetal Deposition Disease States: Diagnosis and Treatment.

I generally do not like to describe novel approaches until I have firm clinical experience with it. I do not have this yet with this topic, and although I like to keep at least some information proprietary, I have developed the approach of letting treating practices and individual sufferers know what I am thinking about, so they can offer state of the art care to their patients around the world. This is especially true for diagnoses and approaches that are life and death. This is one of them. Note that this is largely based on empirical wisdom and not direct clinical experience.

Currently very few individuals I manage have known concurrent toxicity from other heavy metals... having said that I am relatively certain that once an individual has developed a deposition state to Gd, they likely have also activated an immune response to other heavy metals that had been previously quiescent, like lead or mercury. In some individuals, a concurrent heavy metal toxicity can be suggested when the metal is very high on pre- and/or post chelation 24 hour urine test for heavy metals. At the outset, or along the path of treatment, it may be smart to do individual testing of various chelators to see how effective they are at removing specific metals. You need to have pre- and post-chelation 24 hour urine done for each chelator, and some spacing between the chelators is wise to avoid too much cross talk between the chelators. Maybe 1 week is sufficient. This is how I would do it: 1. If you have GDD start with DTPA, as it is the best agent (based on stability constant) currently available to remove Gd, lead, and if you happen to have Plutonium, Amercium, and Curium, and probably other of these actinide metals. DTPA also is most effective at removing inorganic mercury, but variable with organic mercury. Other metals such as Thallium, Cesium, Chromium, DTPA has unknown effectiveness. If these metals are present in elevated amounts on prechelation urine, and DTPA does not increase removal, then explore using a second additional chelator. In the future the first line attempt with chelation may be with HOPO when it comes available, or certainly using HOPO as the second line.

2. The present cautious approach that we use, should likely still be used for atleast 5 chelations with DTPA, prior to considering incorporating a second chelator. In addition simple obvious steps of minimizing exposure to entities that contain other heavy metals should be employed at the very outset of patient evaluation and treatment. For example if Thallium and Cesium are up, the patient must stop immediately eating kale, and even similar cruciferous vegetables (cabbage, cauliflower, etc), broccoli is likely the least likely to concentrate Thallium. If Cadmium or Arsenic are elevated stop eating rice. 3. Second line attempt at chelation could be with DMSA performed 1 week after DTPA. DMSA should be better at removing some species of organic mercury. The attempt with a secondary chelator always interleaved the week in between the 2 week intervals between DTPA chelations. If you are getting DTPA every second week, then you could repeat this chelation attempt with other chelators if DMSA has not removed more of the empirically suspected metal that is toxic to you (that is in a Deposition state, rather than a Storage Condition state). Getting DTPA 1 week following will also serve to remove the Gd redistributed by these agents that result in substantial Gd redistribution (EDTA, DMSA, DMPS). OSR (emeramide) could also be one of the chelators attempted. Prussian Blue as the secondary chelator if Thallium is in question. 4. If the metal in question is identified, by comparing pre- and post-chelation 24 hour urine, and observing appreciable increase of that metal. Some Flare of some symptom should also occur with a Deposition Disease state Then this could be combined in an alternating protocol with DTPA. One week DTPA next week DMSA alternating. DTPA is used to not only treat GDD as per standard, but also to pick up the Gd redistributed by DMSA. 5. Note that steroids should be used concurrently with all the chelators in case the additional metal is in a Deposition Disease state, as without steroid massive Flare could occur. Massive Flare for example with Mercury could result in a paranoid psychosis (Mad Hatter's Disease). 6. Note that prechelation 24 hr urine is always essential to evaluate if the chelator is removing the metal. Done in the setting of evaluating a multi-chelator regimen, the pre- urine must be obtained no longer than 2 days before chelation.

7. As with my current approach to GDD chelation, start with a low amount of all chelators used, and increase from there to patient tolerance. Do not start with standard dose. 8. It may be in the future that HOPO covers such a broad range of metal removal that additional chelators will not be needed in setting of Multi-metal Deposition Disease. HOPO removing all the heavy metals that ail you, would be a dream come true. If an additional metal such as Cesium, Thallium, Chromium, or Mercury is high in pre-iv-DTPA-chelation, and DTPA does not increase their urine amount post-chelation, I would consider trying DMSA, Emeramide and Prussian Blue, as individual agents one at a time, on the off week, using the above regimen strategy. Richard Semelka, MD

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