The Proceedings of the 20th International Conference on Chelation held in the USA: advances on new and old chelation therapies

Abstract

New developments on chelation have been discussed during the 20th International Conference on Chelation in Grand Rapids, MI, USA, which could affect the treatments of millions of patients worldwide. The complete treatment of transfusional iron overload in thalassaemia using the deferiprone (L1) and deferoxamine combination is a paradigm to be followed in the treatment of many other metal toxicity conditions. Encouraging results from clinical testing increased the prospects of the application of L1 as a pharmaceutical chelator antioxidant in renal, neurodegenerative and other conditions. The development of new chelators for the detoxification of heavy and radioactive metals is in the final stages of approval for clinical use. EDTA chelation for heavy metal detoxification has been used in millions of patients worldwide in the last 50 years and continues to attract many categories of patients because of low toxicity and therapeutic benefits. Major changes on chelation therapy policy have been introduced by the FDA in the USA in the last few years, including the approval of L1 in 2011, the release of reports with 2474 fatalities which include thalassaemia and sickle cell anaemia patients in the period 2007–2011 in the case of deferasirox and the reappraisal of EDTA chelation therapy by NIH for patients who have suffered myocardial infraction. Major controversies in the use of chelating drugs worldwide include the risk/benefit assessment of different chelation protocols for different conditions and the commercial conflicts between generic and patented drugs.

Keywords::

• Chelation therapy
• deferiprone
• deferoxamine
• deferasirox
• EDTA
• iron overload
• metal imbalance and toxicity

Introduction

The 20th International Conference on Chelation (ICOC) was organized in Grand Rapids, MI, USA on the 22–25th October 2010. The presentations and discussions during the conference focused on key developments in the area of metal metabolism and toxicity and on chelation therapies with many topics covering wide spectrum of sciences from chemistry to clinical trials.

Among the major issues discussed was the acknowledgement that hundreds of thousands of people have been using chelation therapy in the USA and worldwide in the last fifty years. During this period, chelating drugs have been administered to thousands of patients with a wide range of conditions. Some of these conditions such as transfusional iron overload toxicity in thalassaemia or copper overload toxicity in Wilson’s disease are very serious and fatal, unless chelation therapy could be introduced and in most cases used on a daily basis, in order to eliminate the continuous accumulation of these two toxic metals (Blanusa et al. 2005; Kontoghiorghes 2005). EDTA chelation therapy is also widely, but less frequently used for preventing heavy and other xenobiotic metal accumulation and toxicity, which have been implicated in many diseases (Carven and Morrelli 1975; Lewin 1997). Similarly, the need of specific chelating drugs for the removal of radioactive metals such as Pu and U has been highlighted and reached major and global concern following the nuclear accident in Fukushima (Dauer et al. 2011; Miller 2012). The implication of Fe, Cu and other metals in the catalytic formation of free radicals and oxidative stress leading to tissue and organ damage is a major area under development in relation to chelation therapy, involving almost all diseases including ageing (Denisov and Afanas’ev 2005; Kontoghiorghes 2009a).

In all the cases of metal toxicity and associated side effects, the identification and characterization of the metabolic and toxicity pathways involved, as well as the tissues affected, is important information for specifying and targeting the chelation therapy that is appropriate for each condition. This approach has been illustrated by the use of specific diagnostic techniques for assessing gross and focal iron overload in different organs and different conditions (Forni et al. 2008;Kontoghiorghes et al. 2005; Wood and Ghugre 2008).

Iron chelation therapy

The complete treatment of iron overload in regularly transfused thalassaemia patients using the ICOC deferiprone (L1) and deferoxamine (DFO) combination and the maintenance of normal range body iron store levels using lower overall doses of L1 monotherapy is considered as a paradigm of metal detoxification, which has resulted in the substantial reduction of the associated morbidity and mortality in the affected group of patients (Farmaki et al. 2010; Kolnagou et al. 2010; Tefler et al. 2006). Many thalassemia patients are also treated with deferasirox (DFRA) mainly because of the ease of the once daily administration. However, there are major concerns on the efficacy and toxicity of DFRA, especially following the reports of a large number of fatalities in different categories of patients (Anonymous 2010; Kontoghiorghes et al. 2009).

The introduction of new technologies such as magnetic resonance imaging (MRI) has been a vital tool for identifying the level of excess iron in different organs in thalassemia and other iron loaded patients and the progress of iron chelation therapy (Farmaki et al. 2010; Kolnagou et al. 2010; Kontoghiorghes et al. 2005; Wood and Ghugre 2008). In particular, the use of MRI T2* has led to the identification of heterogenic distribution of excess stored iron in different organs in thalassemia patients and also to a variable mechanism of iron removal from each organ by the three major iron chelating drugs namely L1, DFO and DFRA (Farmaki et al. 2010; Kolnagou et al. 2010; Kontoghiorghes et al. 2005, 2010; Wood and Ghugre 2008).

Another major development in the area of iron chelation therapy is the ongoing clinical trials of L1 in patients with normal range body iron store levels, such as renal, neurodegenerative and other conditions of focal or localized excess tissue iron (Boddaert et al. 2007; Kontoghiorghes et al. 2009; Forni et al. 2012; Rajapurkar et al. 2007a,b). In these conditions iron catalyzed free radical reactions are considered as the cause of oxidative stress and tissue damage, which results in reduced physiological function by the organs affected or in irreversible damage and organ failure (Kontoghiorghes et al. 2009; Kontoghiorghes 2009a). Deferiprone and other chelating drugs could reverse the associated toxicity in such conditions and depending on the effects of established treatments the chelating drugs could also be used as a main, alternative or complementary therapy in these and other related conditions (Kontoghiorghes et al. 2009; Kontoghiorghes 2009a).

Chelation therapy of heavy metals by EDTA

EDTA chelation therapy has been approved by the FDA since the 1950s and used intravenously for the detoxification of Pb and other heavy metals in millions of patients in the USA and other countries in the last fifty years (Carven and Morrelli 1975; Lewin 1997).

Despite the lack of randomized clinical trials, EDTA chelation therapy has in general been used as an alternative medicine and continues to attract many categories of patients due to the association of heavy metal toxicity with many conditions such as cancer, neurodegenerative, immunological, cardiovascular and other diseases. Furthermore, EDTA’s low toxicity and apparent additional therapeutic benefits that have been observed during its long term use, have enchased its therapeutic profile and application in patients with different conditions. However, clinical uses of EDTA other than the removal of xenobiotic metals still remain controversial (Grier and Meyers 1993).

A randomized clinical trial to assess chelation therapy (TACT) has recently been designed by governmental authorities and other organizations in the USA in order to evaluate whether EDTA chelation therapy in conjunction with high dose oral vitamins and mineral therapy could offer clinical, quality of life, and economic benefits for patients with a prior myocardial infraction by comparison to other established therapies (Lamas et al. 2012).

Although the results of the TACT which are expected to be released in 2012 may be positive, the role of EDTA in the categories of patients that have been tested cannot be fully evaluated due to the large number of components in the administered mixture, which includes vitamins and minerals.

The role of metal imbalance toxicity in disease and new chelators as antidotes

The nuclear accident in Fukushima has highlighted once more the need for the improvement of safety in nuclear stations, including the development of new chelating drugs for the decorporation of radioactive metals such as Pu and U from contaminated individuals (Blanusa et al. 2005; Dauer et al. 2011; Miller 2012). The same environmental threats apply from the development and use of nuclear weapons.

Diethlynenetriaminepentacetic acid (DTPA) is the only approved chelator for Pu and other radioactive metal decontamination at present. New chelators with a better efficacy than DTPA and the ability to target and remove the radioactive metals from specific organs, will improve the therapeutic outlook of individuals affected by the contamination (Abergel and Raymond 2011).

Investigations are also under way for new chelators for the decorporation of Hg and other heavy metals which are not chelated by EDTA, or by any of the other approved chelating drugs (Blanusa et al. 2005; Clarke et al. 2012).

The importance of essential metals such as Fe, Cu and Zn for normal physiological functions and their control within the normal range body levels is another area under investigation in relation to the application of chelation therapies. Within this context, essential metal imbalance leading to overload, deficiency or misplacement has been identified as the cause of many diseases. In such cases, the metal imbalance effects could be ameliorated and the associated conditions been treated using specific chelating drugs or in case of deficiency essential metal supplementation and metal complexes (Cai et al. 2005; Kolnagou et al. 2010; Kontoghiorghes et al. 2005).

Update in the clinical use and toxicity of iron chelating drugs

Following many years of financial and regulatory disputes and controversies many changes have been introduced on chelation therapy policy in the last few years by regulatory authorities such as the EMEA in Europe and the FDA in the USA. A major turn on chelation policy in the case of FDA includes the approval in 2011 of L1 for the treatment of thalassemia patients, sixteen years following its approval in India and twelve years in Europe. The approval coincided with the release of a report of 2474 fatalities which include thalassaemia and sickle cell anaemia patients in the period 2007–2011 following the conditional approval of DFRA as an orphan drug in 2005 and its indiscriminate use in thousands of patients (Schwartz 2010). Deferasirox has been cited to be the second most frequent common suspect drug in FDA reported patient deaths with 1320 fatalities in 2009 (Anonymous 2010; Kontoghiorghes et al. 2009). This is the highest record of chelating drug related patient deaths and one of the highest ever recorded mortality per patient population for any new drug (Anonymous 2010).

Several warnings for the lack of adequate toxicity screening and the prospects of serious toxic side effects with DFRA were published much earlier but no sufficient precautionary or preventative measures were taken to minimize the incidence of serious drug toxicity (Kontoghiorghes et al. 2009; Kontoghiorghes 2010).

The reappraisal of EDTA chelation therapy by NIH for possible use in patients who have suffered myocardial infraction is a further change on chelation therapy policy, which could advance the use of chelating drugs in many conditions (Kontoghiorghes et al. 2009).

These latest events suggest that there are many factors which could influence the use of chelating drugs in different conditions worldwide. These include the risk/benefit assessment of different chelation therapy protocols for different conditions, targeting methods, cost and availability of chelating drugs in each country, the commercial conflicts between generic and patented drugs, the influence of pharmaceutical companies etc. Within this context, the design of optimal chelation therapy protocols for each condition and each patient are essential parameters for consideration and for increasing the prospect for future applications of chelation drugs in many diseases. These developments may also improve the therapeutic outlook of chelating drugs in general and their use as main, adjuvant or alternative therapies in many conditions (Kontoghiorghes 2009b).

Conclusions

Hundreds of thousands of patients are treated with chelating drugs worldwide. The use of chelation therapies are increasing and their application has been expanded to include many conditions in addition to those related to metal detoxification. Further studies are needed to optimize the chelation therapy protocol in each condition and for each patient. There is a prospect of using chelating drugs as main, adjuvant or alternative therapies in many conditions

Acknowledgments

The author would like to thank the authors and reviewers involved in the production of the 20th ICOC proceedings, the members of the ICOC and other scientific committees, the participants and all others who contributed to the successful organization of the 20th ICOC in in Grand Rapids, MI, USA, in October, 2010. Presented at the 20th International Conference on Chelation, Grand Rapids, MI, USA, October 22–25, 2010.

Declaration of interest

The author report no conflicts of interest. The author alone is responsible for the content and writing of this article.