This presentation summarizes several of the rodent and non-human studies that we have conducted to help inform the efficacy and clinical utility of succimer (meso-2,3-dimercaptosuccincinic acid) chelation treatment. We address the following questions: (1) What is the extent of body lead, and in particular brain lead reduction with chelation, and do reductions in blood lead accurately reflect reductions in brain lead? (2) Can succimer treatment alleviate the neurobehavioral impacts of lead poisoning? And (3) does succimer treatment, in the absence of lead poisoning, produce neurobehavioral deficits? Results from our studies in juvenile primates show that succimer treatment is effective at accelerating the elimination of lead from the body, but chelation was only marginally better than the complete cessation of lead exposure alone. Studies in lead-exposed adult primates treated with a single 19-day course of succimer showed that chelation did not measurably reduce brain lead levels compared to vehicle-treated controls. A follow-up study in rodents that underwent one or two 21-day courses of succimer treatment showed that chelation significantly reduced brain lead levels, and that two courses of succimer were significantly more efficacious at reducing brain lead levels than one. In both the primate and rodent studies, reductions in blood lead levels were a relatively poor predictor of reductions in brain lead levels. Our studies in rodents demonstrated that it is possible for succimer chelation therapy to alleviate certain types of lead-induced behavioral/cognitive dysfunction, suggesting that if a succimer treatment protocol that produced a substantial reduction of brain lead levels could be identified for humans, a functional benefit might be derived. Finally, we also found that succimer treatment produced lasting adverse neurobehavioral effects when administered to non-lead-exposed rodents, highlighting the potential risks of administering succimer or other metal-chelating agents to children who do not have elevated tissue lead levels. It is of significant concern that this type of therapy has been advocated for treating autism.To get more news about NBMI, you can visit fandachem.com official website.

This paper summarizes some of the animal studies completed in our laboratory over the past decade or so that help inform the efficacy and clinical utility of chelation treatment as commonly practiced. As a brief overview of its mechanistic basis, chelation treatment can be simply described as the process of the chelate ligand forming a selective and stable coordination complex with the metal of interest, yielding a complex that is more readily excreted in urine or feces than the metal alone (or the metal complexed with other inherent biological ligands). The efficiency of forming the metal–chelate complex can be described in the simplest terms as the ratio of the chelate versus the unbound metal (depicted as E in Eq. 1), and can be expressed as a stability constant (β) as depicted in Eq. 2: In reality, of course, these simple expressions do not tell us all that we need to know about how a chelating agent may be acting within the body.

For example, it does not tell us about the presence and effect of competing ligands or other metals within the body, the kinetics of metal exchange with the ligand, the extent to which the chelating agent (i.e., the drug) may be metabolized and transported throughout the body, or how the chelating agent may be compartmentalized within the body. We also know that in vitro studies may not provide sufficiently predictive information about how these important processes occur in vivo. As a result, animal or clinically based studies are needed. Given this, the objective of this presentation is to address important questions on chelation efficacy, using research animal model-based investigations that we have conducted with succimer over the past decade or so. As background, it is important to first recognize that there has been quite a bit of research over the past several decades by Drs. Graziano, Aposhian, Dart, Maiorino, and colleagues, among others, that has provided the foundation for much of what we now understand about chelation treatment with succimer and other chelating agents [1–10].

Those studies characterized the metabolism of succimer (meso-2,3-dimercaptosuccinic acid, or DMSA) in human subjects after it first started gaining attention as a lead-chelating agent. They determined that following a therapeutic dose essentially all the DMSA in the human body is excreted as mixed disulfide compounds, with a majority of the compound within the circulation being mixed disulfides with plasma proteins, primarily albumin. The majority of the excretable DMSA in urine also appears as mixed disulfide compounds [7, 8]. Studies also showed that DMSA undergoes enterohepatic circulation [10]. Notably, it was shown that only a relatively small amount of the DMSA administered to humans is excreted within the first 2 to 4 h following dosing, while a substantial amount of it is still retained in the body after that period of time. Studies also provided some evidence that a patient’s lead poisoning status may alter how s/he metabolizes DMSA, with reduced renal clearance of DMSA and the DMSA-lead chelate in more severely lead-poisoned subjects.