Chelation therapy agents

Structural Insights into the Rational Design of Chelation Therapy Agents... 

One of the greatest goals of this field is to develop a sufficiently good understanding of lead coordination chemistry to be able to rationally design improved ligands for lead that could be used as chelation therapy agents to treat... 

The thermodynamics of lead-ligand interactions provide key insights both into the probable mechanisms of lead s toxicity and into the design of improved chelation therapy agents. Various constants can be used to describe the affinity of a metal ion for a given ligand described by the net equilibrium (300, 301) ... 

A summary of known binding constants for Pb(II) to common functional groups, biological molecules, macrocycles, and chelation therapy agents is provided in Tables IX-XI (264, 270, 306, 315-329). Structures of chelating ligands and macrocycles discussed in the text are presented in Table VIII. 

The most commonly used chelation therapy agents in the United States today are EDTA and DMSA (or succimer). In addition, penicillamine (PCA) and BAL are used to chelate lead. Each of these agents has numerous disadvantages, ranging from undesirable methods of delivery (intramuscular injection of BAL and intravenous delivery of EDTA), to unpleasant side effects (typically nausea and vomiting), to chelation and increased excretion of necessary metals (e.g., iron and zinc) (Table XIX) (17, 207, 525). 

Given these limitations, why have better treatments not been developed The reality is that this is a formidable task The ideal chelation therapy agent should satisfy all of the following criteria (442) ... 

To enhance iron excretion, intensive chelation therapy is used. The most successful drug is desferrioxamine B, a powerful Fe3+-chelator produced by the microbe Streptomyces pilosus,6 The formation constant for the Fe(III) complex, called ferrioxamine B, is 103afi. Used in conjunction with ascorbic acid—vitamin C, a reducing agent that reduces Fe3+ to the more soluble Fe2+— desferrioxamine clears several grams of iron per year from an overloaded patient. The ferrioxamine complex is excreted in the urine. 

Ethylenediamine tetraacetic acid (EDTA) was introduced originally as a water-softener and as a textile dyeing assistant because of its ability to form very stable, water soluble complexes with many metal ions, including calcium and magnesium. The equilibria involved in chelation of metal ions by EDTA and related ligands have been exhaustively studied, notably by G. Schwarzenbach and his colleagues, and provide the basis for complexometric methods of chemical analysis. EDTA and its metal complexes have also become probably the most familiar examples of agents used in chelation therapy. 

The high affinity for oxidized iron makes the siderophores ideal candidates for chelation therapy where the body is becoming overwhelmed by iron(III) either through acute poisoning or conditions like haemochromatosis that can occur when patients receive frequent blood transfusions. While enterobactin would seem to be the primary choice it has two major drawbacks its synthesis is complicated and, although both isomers bind iron(III) to the same extent, only the L-isomer has activity in vivo. Consequently desferrioxamine B is the agent of choice. 

A Note about Chelation Therapies. Chelation therapies are used to prevent or treat metal-induced toxicities. They are often used in acute poisoning scenarios, but can also be used to assess exposure. One of the major challenges in the management of chelation therapies is the tendency for chelating agents to interact with essential metals, particularly calcium and zinc. Chelation therapies should only be administered by a physician due to the potential to disrupt essential metal functions. The Food and Drug Administration does not regulate dietary supplements, and several do it yourself chelation therapies are available. These are not advisable. 

Treatment While damage cannot be cured, disease progression can be slowed down by lifelong chelation therapy. These chelating agents (including d-penicillamine or trientine hydrochloride) can help remove copper from tissue, and zinc supplements may help slow copper absorption, but patients also need to follow a diet low in copper. In extreme conditions where patients do not respond to treatment, liver transplantation may be an option. 

Excess transition metals can be removed by chelation therapy using chelating agents such as deferoxamine, EDTA or D-penicillamine, and supplements can be used in cases of deficiency (e.g. iron(II) suphate or zinc(II) sulfate). 

The treatment of thalassemia, as in other metal overload disorder, is chelation therapy. The chelating agent most widely nsed is deferoxamine administered subcutaneously. The search for an orally administered iron chelator has intensified in recent years, leading to cUnical trials of many potential new iron chelators snch as deferiprone(Ll). However, many issues regarding the nse of these drugs, such as dose-related toxicity and recommended age of initiation, remain unresolved. " ... 

Similar to the mustard agents, exposure prevention is the first line of defense against lewisite. Rapid decontamination is especially relevant to lewisite exposure due to the rapid development of pain (1-2 min) associated with lewisite exposure. Unlike other vesicants, an effective antidote for lewisite toxicity exists in the form of British anti-lewisite (BAL 2,3-dimercaptopropanol) which binds with arsenicals, thereby countering the lewisite-induced damage. Such chelation therapy is associated with notable side effects (e.g. renal effects) and requires carefiil medical management. More effective analogs of BAL have been developed with less significant side effects. 

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