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Chelation Precedents. Various examples of millions of doses of chelation equivalents.

A question I commonly get is how safe is DTPA to use as a chelator. I commonly use the example of the use of DTPA as a binding molecule in many applications. This is the first ligand used for MR contrast, and has been used in atleast 100 million applications, and the reason it is used to begin with, is it is the component of the Gd complex that makes it 'safe'. Technetium in nuclear medicine has been coupled with DTPA for similar reasons.. But this is not the point in this blog, since I have dealt with this subject previously.

What I want to address is, in a more recent blog, I describe that management for a severe acute hypersensitivity reaction should include in addition to the standard combination of a steroid and an antihistamine (which I estimate has probably been used in perhaps 1-10 million acute hypersensitivity reactions (AHRs) to the full spectrum of drugs, toxins, insect bites, etc) but with the addition of Ca-DTPA, when dealing with Gd toxicity. I would recommend Ca-DTPA over Zn-DTPA, because Ca-DTPA removes more Gd. by virtue of the fact Ca is less tightly bound to DTPA than Zn. Unlike with most other chemical AHRs, where we lack the ability to remove the inciting chemical, so we have to wait for it to be bound somewhere in tissues (eg: fat. bone), broken down and eliminated or stored, or naturally eliminated, with GBCAs we can actually remove the inciting chemical.

I had used in that blog the timeline, that to perform ultra-soon chelation it should be performed before 14 days (using vaccine information on how long it takes for full immunity to develop) and ideally within 2 days.

It recently occurred to me, years back we wrote a major large scale project comparing 10s of millions of injections of two linear nonioinc agents (the agents with the highest causation for NSF) Omniscan (Gadodiamide) and Optimark (Gadoversetamide); and the lower incidence of NSF with Optimark we ascribed to the fact that Optimark contained 10% Ca-versetamide, and Omnsican 5% Ca- diamide, so the higher amount of 'free' ligand (effectatively a simultaneous chelator) provided protective benefit against NSF. I had previously touched on that in the early days of NSF recognition the years 2007, 2008, the manufacturer and their hired speakers focused on that Omniscan had fewer AHRs than macrocyclic and other ionic GBCAs, so overall still may have more benefit- and most of us MR experts dismissed this as ridiculous marketing ploy. Within a few years the use of Omniscan and Optimark largely disappeared. In a blog from 1-2 years ago I did have a revisionist view, that maybe they were right, that there were lower acute AHRs, and part of what I focused on is that protein-binding of other agents (eg: Multihance) does correlate with more AHRs. But most of these AHRs are simple and transient, like transient increased warmth. But I now consider it likely that the increased content of free ligand also served to decrease acute AHRs, and not a property related to the molecule being nonioinic as they had focused on. It was the free ligand that kept AHRs low.

Now by extrapolation, it does seem empirically reasonable that the excess ligand, theoretically would, and did, result in a lesser occurrence of GDD, as GDD not uncommonly begins as an AHR. So Omniscan and Optimark and the combined > 100 million doses of them, constituted simultaneous chelation with a GBCA ligand. By the way Magnevist is manufactured with 0.5% Ca-DTPA dimeglumine. So there actually is tremendous experience with simultaneous chelation with a GBCA chelator. In fact injection of a typical dose of Optimark in a typical adult would be 2ml of chelator, which is basically half dose DTPA as we perform chelation. So something like 30 million half dose chelations have been done with just this example.

My recommendation though is not to do simultaneous chelation in everyone (except for perhaps high risk people, and I do not recommend GDD individuals getting more GBCA even with simultaneous chelation). But this supports, by extrapolation, the concept of very soon chelation in individuals with severe AHR after the GBCA injection, either within minutes or clearly up to 2 days post GBCA injection. This should greatly decrease the severity of AHR, but also by extension of GDD.

I have made the point in many blogs that DTPA also removes fully intact GBCAs, such as Prohance and Dotarem by levering the intact GBCA out of interstitial tissue, back into the circulation and out through the kidneys. The much higher stability constant of DTPA compared to EDTA would make it far superior to remobilize fully intact GBCA. As it is a magnetic attraction property, perhaps a better word to use is tugging. A linear chelator should work more effectively than a macrocyclic agent since the negative charge is on the surface, rather than centrally. Think of a fridge magnet, a stronger magnet sticks to the fridge better (DTPA vs EDTA), and the magnet sticks better if the magnet part is right on the surface rather than coated by a fabric (linear design chelator rather than macrocyclic). This then raises a point that I have also made before, maybe an even stronger magnet for Gd should be used than DTPA, the obvious is the ligand for Multihance, BOPTA, since Multihance has higher orders of stability constant for Gd than does Magnevist.

In summary, using reasonable extrapolation, it would seem prudent to use ultra-early chelation with Ca-DTPA for AHRs and by extension GDD, when using iv steroids and anti-histamines. DTPA has been shown to tug even intact macrocyclics out of tissues back into the circulation. Yes a small percentage will be redistributed, but as is observed with fully intact GBCAs, the great majority will be eliminated in the urine.

Richard Semelka, MD.

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