On chelators

Chelate is from the Greek for claw, which describes the function of chelator to grab onto something else. Chelation is the principle method to treat metal diseases because, metals cannot be broken down in the body, so they need to be eliminated if an individual is sick from the metal. The way to remove them is for another chemical to bind them in order to remove them, that is chelation.

In general the method of elimination of metals that are chelated is through renal elimination, in most cases, and by hepatobiliary elimination in which the metal is excreted in bile and comes out through the colon. Metals can also be eliminated in small amounts, and in which they are not chelated, primarily through sweat, especially apocrine gland, tears, saliva, breathing exhalation, nails, hair, and skin exfoliation, with only sweating resulting in meaningful elimination.

Chelators can either form chemical bonds (generally those that remove through the circulation) or physical bonds, generally those that are eliminated through the digestive tract, usually through fecal elimination, but vomiting as well.

Mainly when we think of chelators with think of molecules that form chemical bonds, and these will be the primary focus of this blog.

Types of chemical bonds and the chelators that use them.

Covalent bonds. This bonding is formed when atoms share electrons. A form of covalent bonding is coordinate bonding where only one atom contributes the electrons to be shared. Coordinate bonding is how the agents DMPS and DMSA bind heavy metals.

Ionic bonds. Virtually all metals are cations in chemical bonds. So when ionic bonds are created the metal is a cation. Chelation then reflects cation exchange bonding, where the chelator exchanges the cation it is manufactured with (most often Ca) with the heavy metal, for example Gd or lead (Pb). The term transmetallation has been used in MRI GBCA reactions for this process. I find the concept confusing so prefer the clear expression cation exchange.

Electrostatic bonding. Common examples are rubbing a balloon against a wool pant and it sticks to the pant leg, or the mild shock of wool to finger touch or hair standing on end putting on a wool sweater in dry climate.. This electrostatic process is combined with molecular folding (like a soft taco) to create the form of bonding that HOPO utilizes..

Administered in active and inactive state

Agents are administered in their active or inactive state, where the latter category have to be converted into active state in the body. This is generally by the liver. DTPA and EDTA are injected in the active state and also eliminated in active form. In contrast DMPS and DMSA are injected as inactive drugs and converted into active form in the liver. This is referred to as agents being prodrugs. There are decided advantages to injection in active forms as this does not rely on the organ (liver) being healthy, and also decreases the possibility of toxic damage to organs that detoxify, principally the liver.

Agents with lesser chelation effect

There are a number of supplements, food substances, and drugs with lesser effect of chelation. The most notable are vitamin B sub types (notably niacin) cilantro, oregano, and emeramide. This category could also include oral physical binders such as pectin, pectin-containing foods, and activated charcoal. These binders will essentially have benefit restricted to heavy metals that are acquired orally. Diatomaceous earth is also in this category, but is not recommended because it also contains rare earth metals such as Gd. The B vitamin subtype Niacin has shown particular efficacy with Arsenic, as it assists with methylating Arsenic which facilitates excretion. Deferoxamine is a specific agent that binds to iron to facilitate elimination of iron in urine. This is used in Genetic Hemochromatosis. Its use for other heavy metals not recommended as stability is low with others. Penicillamine is used to remove copper in Wilson's Disease.

Critical features of an effective chemical chelator.

There are two features that are critical for a chelator to be an effective chelator:

1. The agent must have high log stability constant (AKA thermodynamic stability) with the heavy metal in question. The target value for a very good chelator is 20.

2. There must be objective documentation that the chelator removes the heavy metal from the body. For this purpose we use 24 hour urine for 20 heavy metals. Pre-chelation urine obtained within 2 days of chelation, and post-chelation obtained immediately after chelation. The timing for the postchelation start is after the first urination, which should be either during chelation or immediately after chelation. The explanation is that this urine will have been created prior to the administration of the chelator.

   Blood (often serum) values for heavy metals also can be used, but since they are snap shots in time of the heavy metal, extreme care must be taken to ensure near exact timing for blood sampling for comparison to be useful. Probably optimal timing is 45-60 minutes post chelation. Without exact standardization these values can be misinterpreted as to how much metal is present or removed, and hence dangerously meaningless.

The third point is self-evident but worth mentioning,

3. The agent must have documented safety.

Selected description of effective chelators in usage, incorporated above information:

DMSA:

Prodrug. Binds heavy metals with coordinate bonds with sulfhydryl groups. Elimination is through the kidneys. Log stability constant with Mercury= 18, Pb= 18, Gd = 12.. So agent a good chelator for mercury and lead, but only fair for Gd.

EDTA:

Active drug. Binds heavy metals with ionic bonds by cation exchange. Elimination is through the kidneys. Log stability constant with Mercury 12-14, Pb 18, Gd 17. So agent is good with lead and fair with Mercury and near good Gd.

DTPA:

Active drug. Binds heavy metals with ionic bonds by cation exchange. Elimination is through the kidneys. Log stability constant with Mercury (inorganic) 26 and (organic)(10-14), Pb 18.6, Gd 22. So DTPA is very good with Gd, near very good with Pb, extremely good with inorganic but fair with organic mercury.

HOPO:

Active drug. Binds heavy metals with electrostatic forces and folding over the metal. Elimination is through kidneys and partly hepatobiliary. Log stability constant with mercury 12-14, Pb 18 , Gd 22. So HOPO is good with Pb, very good for Gd, and fair with Mercury,

Prussian Blue:

Active drug. Activity restricted to gut, unlike above which work systemically. Ion exchange mechanism. Traps positively charged metal ions by exchanging for potassium in its molecular structure. It is used for Thallium and Cesium-137. It will work for nonradioactive Cesium, however the radioactive form is the one targeted because of the concern of the severity of radio-toxicity. Its ability to remove other metals that have been incorporated through the gut (which are many of the heavy metals) is uncertain. Log stability constant is not described.

Basis of Toxicity:

The principle basis of toxicity for most heavy metals is the combination of creating an Immune Mediated Inflammatory DIsease (IMID) which then creates access to cells to generate an additional direct toxic effect, so it is a one-two punch effect. The exact mechanism of how this occurs is uncertain. That is: is it a passive allowance that the IMID creates for the toxicity, or an active participation. As illustration, does the IMID cause immune cells not to protect cell surface portals to entry of the toxic metal, or do the immune cells actively facilitate this entry. Furthermore, what is of critical importance to illuminate, what processes does the immune system of individuals who have the heavy metal but are not sick from it (Storage Condition) enact to prevent this toxicity from happening. One obvious finding extrapolated from the literature, is in Deposition DIsease states the majority of cytokines released are pro-inflammatory, whereas in Storage Condition they are regulatory or inflammation suppressing cytokines, or the combination of cytokines released have these effects.

Patterns of Response to chelation treatment.

There are 3 patterns reflecting chelator action with heavy metals.

1. Heavy metal removal. The higher the log stability the higher the removal. This is the desired activity. This occurs immediately with highest effect within 1 hour, but continuing in substantial amount in 1 day, and tapering off by day 3.

2. Heavy metal redistribution. This is an undesired effect. This reflects the chelator picking up the heavy metal then immediately re-releasing it. This occurs with chelators with lower stability, with the lower the stability the larger the amount of redistribution. The effect can be pick up of metal in skin, releasing it right away and heavy metal going to brain..

3. Heavy metal re-equilibration. This reflects le Chatelier's principle: everything strives to be in equilibrium. This can be a very effective means of reducing total body heavy metal content. The process reflects chelator removing the heavy metal from large reservoirs that are loosely binding the heavy metal, which generally are soft tissues: skin, muscles, soft tissues organs such as brain, liver, kidneys. With time heavy metal in more durable reservoirs, such as bone, shift to the soft tissue reservoirs that have been depleted by chelation, to re-establish equilibrium. This most often becomes clinically apparent 3 weeks post chelation.

Triphasic response to chelation

A triphasic response to chelation has been well established in the peer-reviewed literature for Gd. More limited experience is shown with Pb. Our opinion is that it is likely observed for many heavy metals.

With an effective chelator the following is observed:

Heavy metal removal Flare Day 0-7.

Period where improvement is observed Day 7-21..

Heavy metal re-equilibration Flare, Day 21-on.

With subsequent chelations Removal Flares decrease in length and severity, and the period of improvement increases and becomes more durable.

This response to chelation is also essential to observe to confirm that the patient is sick with a Deposition Disease to the heavy metal. Empirically it makes sense, if the individual is sick from the heavy metal, remobilizing it will re-ignite/ intensify the clinical symptoms. Usually these are the symptoms the subject already suffers from, but this may also reflect new types of symptoms, that are also part of the recognized symptom types associated with the heavy metal. The explanation for new symptoms is that the heavy metal has gone to multiple tissues including those not initially symptomatic, and immune cells align along this asymptomatic deposition, in addition to the alignment where symptoms have been present. So removal from these asymptomatic sites may now generate symptoms, because the aligned immune cells recognize their movement and react with cytokine release. Our theory is that the tissue based immune cells are primarily tissue resident memory T cells. Each organ system has their own type of resident memory T cells. If a subject does not have Deposition Disease then removal of the metal and re-equilibration will not cause symptoms in their two time frames.

The critical determination of when to pause/ stop chelation is when the re-equilibration Flare is mild at 1 month post chelation and remains mild at 3 months. It is not however rare that a second shorter stretch of chelation sessions may be necessary about 1 year post the last chelation, as the ongoing continuous re-equilibration of bone back to soft tissues may eventually cause a recurrence of symptoms. Since the total body content of Gd will have been greatly diminished from the earlier chelation sessions, only few further chelations are necessary. Through the periods of re-equilibration it should also be noted that there is also increased native elimination of Gd, since Gd must pass through the circulation to move from bone to soft tissues, and a fair amount of this moving Gd in circulation will also be removed by the kidneys.

Noteworthy is that a triphasic response is also the basis of healing for skin wounds, and other wounds. In these cases, the 3 components do the following: tissue destruction, massive fibrin production, remodeling. As with removal and re-equilibration, with skin healing these 3 processes occur at the same time, but the relative proportion of these actions varies with time, like a ballet performance. Re-equilibration of heavy metals likely begins within 24 hours of removal, but it does not become clinical apparent in most individuals till 3 weeks. In the case of massive heavy metal deposition the clinical manifestation can appear sooner, such as at 1 week. This is because re-equilibration Flare arises on the basis of how much of the heavy metal is present to elicit the intense inflammatory response of Flare.

Immunological effects as separate from toxic

An interesting aspect about heavy metals having a combined immunologic/toxic effect is that while dose of the heavy metal is extremely important (Paracelsus- the dose makes the poison), the immunology can also have an important effect. This means if the heavy metal is in a contained space, even a small amount can cause the disease. So in terms of GBCAs, either a contained extravasation of contrast, or an MR arthrogram can cause the disease even if the amount is only 1 ml. How can this happen? The exact analogy is a vaccination against viruses. The vaccine is administered in a small dose but in a contained location such as intramuscular, subcutaneous, intradermal. So not in a vein which would carry miniscule amounts through the entire body - thus no immunity created). By being injected in a contained space, there is a sufficient amount of the vaccine stable in presence, such that immune cells can travel in sufficient numbers to the site, to generate an immune reaction to benefit the entire body. Gd can do the same thing, acting like a vaccine.

Laboratory confirmation.

24 hour urine documentation of heavy metal content pre- and post-chelation are as objective demonstration of the effect of a chelator as essentially the best of anything else in medicine. It is noteworthy that post-chelation urine remains high for the heavy metal until the largest durable reservoir has been depleted. This is clearly shown for Gd. This is the best documentation of decreasing the total body reservoir of heavy metal. This is the important clinical result. Using Gd as the example, when post chelation urine has decreased (from upwards of 20 mcg. 24 hours) to 3 mcg/ 24 hour is supportive evidence that pausing/ stopping chelation should be entertained. Note these numbers are much lower for the most stable agents: Prohance and Dotarem/Clariscan - so the clinical response forms the major basis for pausing.

Early studies looking at cytokine release in subjects who have received GBCA injection, have shown elevation of cytokines post chelation. Perhaps the most interesting are the dynamic serial acquisition of cytokines, which at present have been only performed by us to look at Gd, therefore a unique measurement. At present an insufficient number of patients have been studied to determine definitive findings. The current opinion is that the total amount of cytokine release may reflect the total amount of Gd remobilzed from the tissues. More clear definition of the types of cytokines that distinguish disease from storage states have yet to be established, however intuitively a greater amount of pro-inflammatory cytokines occur in patients with disease, and more inflammation suppressing cytokines in subjects with storage,

Avoidance and Detoxification Management

Avoidance is a primary form of management for all heavy metals. This is straightforward for Gd, for example if you have GDD never get another GBCA injection again, this is true avoidance, whereas for the majority of heavy metals avoidance is relative, and should be describe as minimization, since sources of these other heavy metals is generally pervasive in the environment, such as Pb.

Detoxification is less specific and less certain for heavy metals, as metals cannot be broken down. I have used the comparison is that heavy metals in humans is like kryptonite for superman. None-the=less general and lifelong detoxification strategies are essential. High on them eating a healthy diet, and maintaining at least mild physical activity. Sauna is helpful in many, but only if the individual can still sweat, otherwise it can be extremely detrimental. Various anti-oxidant and anti-inflammatory foods and supplements should be part of a life-long routine. This may include turmeric, chlorella, and vit B complex.

Radioactivity

A number of the heaviest heavy metals also are radioactive, for example Plutonium. So the principle concern with these metals is not the immune mediated inflammatory disease (IMID) - toxic combined effect that many of the heavy metals cause, but the deterministic (meaning consistent experience for everyone) damaging effect of radiotoxicity. Radiotoxicity is more rapid and lethal and generally all individuals exposed experience this, rather than estimated 1 in 10,000 experience IMID/toxicity for non radioactive metals. So whereas safety and concern for removing native metals is considered with removing metals such as Gd and Pb, which is a slower and steadier process of step-wise removal, more rapid removal of radio-active metals is necessary to contain the radiation destructive properties (essentially tissue sloughing of tissues in contact with the metal (skin, lungs, digestive tract, and the risk of malignancy. In my experience, although Zn-DTPA is considered for daily removal of Plutonium, the preferred agent should be Ca-DTPA because it can remove more heavy metal. Zn-DTPA is used because it does not remove significant amounts of native metals, but it generally removes half the amount of heavy metal as Ca-DTPA. The better strategy would be to use Ca-DTPA and supplement treatment with replenishment of native metals. This would look something like: 3 consecutive days 1 g Ca-DTPA iv as drip technique, with 1 day of native metal replenishment. Simultaneous replenishment of native metals will reduce the amount of Plutonium removal due to competitive binding of cations such as Mg and Zn with Plutonium.

Summary

This review of chelators provides state of the art knowledge of heavy metals where chelation science is clearly shown, notably Gd, and describing where scientific improvement is necessary. Purpose-created chelators need to be created for metals where the 3 essential points of a chelator are focused on. Chromium is just one example. Combination of chelators may be advised in some settings of multi-heavy metal deposition disease. Further effort expended on laboratory test development is necessary.