Technical Explanation Of  Chelation Therapy

Original Publication Date: 5/1/00

Date of Most Recent Review: 4/4/00

Expires: 5/1/03

Medical applications of chelation, especially to combat heavy

metal poisoning, are a product of the 20th century and only

came into existence during the 1940s. This review will look at

the history of conventional chelation therapy and how it has

evolved during the last 60 years from a purely therapeutic

modality to one having prophylactic, therapeutic and diagnostic

significance.

Chelation therapy evokes a variety of images and practices,

not all of which are considered efficacious or, for that matter,

medically ethical by mainstream or conventional practitioners

of medicine. By some, chelation therapy might even be called an

oxymoron. Such is the nature of the division that currently exists

in medicine between conventional and alternative approaches

to chelation therapy in North America.

WHAT IS CHELATION THERAPY?

series of intravenous infusions, intramuscular

injections or oral administrations of chelating agents such as

ethylenediaminetetraacetic acid (EDTA), dimercaprol (BAL)

and penicillamine. These chelating agents serve as ligands that

can bind strongly to metals, including those of clinical interest

such as lead, iron, mercury, copper, aluminum and cadmium.

The therapy is designed to reduce the body burden of these metals

by mobilizing them from accessible storage sites such as extracellular

fluid, liver and kidney and promoting their urinary

excretion.

The administration of a therapeutic chelating agent, HY, to a

patient who has been exposed to a toxic metal salt, MX, drives

the following equilibrium reaction to the right:

HY + MX <——> MY + H+ + Xwhere

the complex formed, MY, is excreted in the urine or

through the biliary tract. The effect is to reduce the body burden

of the toxic metal, M+.

All chelating agents share one property in common: the ability

to form a stable five- or six-membered ring structure with the

central metal ion using donor atoms on at least two functional

groups, termed polydentate ligands.1 Denticity refers to the

number of donor atoms the chelator uses in bonding to the

metal. Those with two donor sites are called bidentate ligands.

EDTA with six donor sites is a hexadentate ligand. The stability

constants for chelate-metal complexes favor the formation of

five-membered rings in preference to six-membered rings, provided

there is no contribution from p-¹resonance effects.

Resonance stabilization comes from overlap of available empty

metal d-symmetry orbitals with extra pairs of p-orbital electrons

on the oxygen, nitrogen or sulfur donor atoms of the ligand.

This contributes to the overall thermodynamic stability of

the complex and could make a six-membered chelate-metal

bond more stable. Seven-membered rings are rare, however, and

larger chelates do not exist in nature (Table).

As Goyer noted, there are currently three areas of interest in

the clinical use of chelating drugs: treatment of heavy metal toxicity,

removal of metals that accumulate in body tissues because

of genetic disorders and chelation therapy for degenerative diseases

of the blood vessels.2 The first two uses are generally considered

conventional medical applications and the last an alternative

medical application. As the clinical significance and

biological effects of heavy metal exposures have been more ex-

s

that has a higher affinity than calcium for EDTA and can displace calcium

from the central core of the molecule. Lead in the +2 oxidation state has a

coordination number of 6 and the 1:1 complex with EDTA (PbNa2EDTA)

has an octahedral structure.

A combination of EDTA and British Anti-Lewisite (BAL) (2,3-dimercaptopropanol,

dimercaprol) has been used to treat children with acute

lead encephalopathy who are comatose or have intractable vomiting.4

Lewisite (dichlorovinylarsine) is a potent organoarsenic compound that

became infamous during World War II as a potential chemical warfare

agent. BAL was developed as an effective antidote (although it was never

used to treat Lewisite poisonings), but it was later found to be useful

against both lead and mercury poisonings.5

The practice of treating children having blood lead levels of 70 mcg/dL

–100 mcg/dL with this chelation cocktail has reduced the mortality from

lead encephalopathy from about 30 percent to 1 percent or 2 percent as

compared with treatment with EDTA alone.6 BAL is insoluble in water

and is available only in peanut oil for intramuscular injection. BAL is the

most toxic of the chelating agents approved for clinical use but has the advantage

of being the only commonly used chelation agent able to diffuse

across cellular membranes (erythrocytes) to bind with intracellular

metals.7

In January 1991, the FDA approved the drug DMSA (meso-2,3-

dimercaptosucinnic acid, succimer, Chemet®) for the treatment of

childhood lead poisonings with blood lead levels >45 mcg/dL.8 An advantage

of this agent is that it can be given orally, making it not only

tensively explored, the distinction between safe and toxic levels of heavy

metals has become less well defined.

Specialists in alternative medicine use chelation therapy to lower body

burdens of heavy metals such as lead and mercury, which heretofore were

considered "normal" or clinically insignificant. The discussion that follows

will be limited to highly toxic exposures and the prevailing medical

recourses for treatment.

Chelation therapy using EDTA for the treatment of inorganic lead poisoning came into prominence during the 1950s. In drug form, CaNa2EDTA (Calcium Disodium Versenate®) is FDA-approved for use in both pediatric populations and adults for the reduction of blood lead and depot stores of lead in lead poisoning and lead encephalopathy.3

The pharmacological effects of Versenate are due to the formation of chelates with divalent and trivalent metals, including Pb+2, which are subsequently excreted in the urine.3 Stable chelates are formed by any metal easier to administer but also conducive to patient compliance. In addition, it is much less toxic than BAL, having a high therapeutic index. It is not indicated (i.e., approved) for prophylaxis of lead poisoning in a lead-containing environment.8 Its use should always be accompanied by identification and removal (remediation) of the source of the lead exposure (primary prevention). This chelator has also been shown to be effective in the treatment of cadmium, mercury and arsenic poisonings.9

For children with blood lead levels of 25 mcg/dL – 44 mcg/dL, an eight-hour mobilization test can be done to gauge the effectiveness of chelation therapy. In this lead provocation test, CaNa2EDTA is administered at a dose of 500 mg/m2 in 5 percent dextrose infused over one hour. All urine is collected during the next eight hours and the urinary lead excretion measured. The test is considered positive if the ratio of the lead excreted (mcg) to the amount of CaNa2EDTA administered (mg) is >0.6. Children with a positive test result may benefit from a five-day course of chelation.8,10

For asymptomatic children with blood lead levels of 10 mcg/dL –24 mcg/dL, the use of chelation therapy is contraindicated in spite of the fact that at a blood lead level (BLL) of 10 mcg/dL –15 mcg/dL measurable effects of lead toxicity do occur, including the impairment of cognitive and behavorial development.11 In this context, the most critical unknown factor as expressed by Mortensen is "whether chelation will prevent, reduce or reverse the neurotoxic effects of lead in apparently symptom-free children—information required for a scientific decision about when (or if) to use chelation therapy, and for whom."12

For adults, occupational exposure to lead in general industry and the construction industry is covered by the 1978 OSHA Lead Standard (CFR 1910.1025) and by the 1993 OSHA Lead Standard for the Construction Industry (CFR 1626.62), respectively. A medical surveillance program is included as part of a comprehensive approach to prevention of lead-related disease and includes periodic monitoring of BLLs. Any general industry worker found to have a single BLL of 60 mcg/dL or greater must be removed from the high-exposure job (termed "medical removal protection").13 A worker is not allowed to return to a job with the potential for high lead exposure until his or her BLL has fallen below 40 mcg/dL on two successive occasions.13

Many occupational health professionals consider the standards out of date and are taking a more proactive approach to identifying workers at risk for potential health problems associated with exposure to lead.13,17 Their reasoning is that the median BLL of the general population has fallen to <5 mcg/dL since lead was removed from gasoline in the 1970s and that the OSHA "safe" level of 40 mcg/dL no longer applies. While the U.S. Public Health Service (USPHS) has set a year 2000 goal of reducing occupational BLL to <25 mcg/dL, some consider even that to be too high and are using 10 mcg/dL as an action level.13

Versenate® and D-penicillamine (Cuprimine®, Depen®) are the most widely used chelating agents for treating lead toxicity. Versenate® is an ionic chelator and does not enter the cellular compartments.

It is distributed mainly in the extracellular fluid and binds to diffusible lead, creating a concentration gradient between erythrocytes and plasma as the complexed lead is excreted in the urine. After a three- to five-day course of treatment, it is necessary to suspend therapy until an equilibrium has been re-established between the cells and plasma. Additional courses may be initiated after at least two to three days of interruption.

The amount of lead typically excreted during a five-day treatment is 5 mg –10 mg, which is only a small fraction of the body burden in bone that may amount to 500 mg to 1000 mg.5 Twenty-four hour urine collections are used to monitor lead excretion, along with that of zinc and copper, both essential elements that may be depleted by chelation.15Mineral supplementation is used to restore these elements.

Some individuals who undergo repeated courses of chelation demonstrate a rapid decline in blood lead during the initial course of chelation, but will plateau or level off during later courses of chelation. This is attributed to the "rebound effect" as lead re-equilibrates from bone stores into the blood. This rebound has been used as a guide to the duration of chelation. Kosnett has reasoned that if a significant postchelation rebound occurs after a five-day treatment period, "the patient has a preponderance of lead in the slow pools (bone) and chelation will have a minimal impact on the total body lead stores or the blood half-life. This is characteristic of chronic, heavy exposure."5

If, on the other hand, the patient exhibits no rebound phenomena, "repeated courses of chelation may be useful to clear the fast compartments (soft tissues, blood) and significantly reduce the body lead burden. These individuals most likely had brief, intense exposure and do not have much lead in their skeleton."5

Lead is a cumulative toxin and symptoms may take years to develop following low level exposures. For workers with acceptable occupational BLLs (<40 mcg/dL) but showing general signs and mild symptoms of chronic lead toxicity such as renal insufficiency and hypertension, diagnostic or provocative chelation testing is allowed as an aid to the diagnosis of chronic lead poisoning.

The lead mobilization test can establish a relationship between past lead exposure and present illness. An elevated urinary lead excretion (>600 mcg/24 hours) demonstrates an increased body burden and is consistent with a previous history of lead exposures. 18 Whereas lead in blood and soft tissues has an estimated half-life of 35 to 40 days, lead in bone has a biologic half-life of more than 10 years. Since excretion is slow, the lead that accumulates in bone provides a source of remobilization and continued toxicity after exposure ceases. Lin et al have shown that chelation therapy as an intervention seems to slow the progression of renal insufficiency in patients with abnormal renal function and mildly elevated body lead burden.19

•Copper Chelation

Wilson’s disease is a rare genetic disorder of copper metabolism and transport involving the liver and brain. The incidence of Wilson’s disease is reported to be three or four cases per 100,000 population.20 It was first described in 1912 by Dr. Kinnier Wilson as a primary neurologic disease accompanied by cirrhosis and referred to as "hepatolenticular degeneration." The defect results in im-paired intrahepatic copper transport and leads to reduced biliary copper excretion and accumulation of hepatic copper.

Left untreated, Wilson’s disease can progress to fulminant hepatitis with a mortality rate of about 70 percent. Psychiatric symptoms are often the first manifestation of the disease and can range from major depression, mania and antisocial behavior to psychosis.

These acute altered mental status changes can obscure the diagnosis and make early diagnosis and timely treatment essential to averting a catastrophic outcome. Recommended screening evaluation for children and adolescents with suspected Wilson’s disease includes serum ceruloplasmin and 24-hour urine copper determination after D-penicillamine challenge.20 A low ceruloplasmin and high 24-hour urine copper excretion are diagnostic for Wilson’s disease; clinically, the patient may present with the aforementioned neuropsychiatric symptoms and Kayser-Fleischer rings.21

D-Penicillamine (DPA, dimethylcysteine, Cuprimine®, Depen®) is the first drug of choice for the treatment of Wilson’s disease and was introduced by Walshe in 1956.22,23 It is a sulhydryl group containing amino acid, which can chelate metals such as iron, lead, mercury and arsenic in addition to copper. To avoid its misuse in the workplace, however, it is not FDA-approved for lead poisoning.10

As a tridentate ligand, it most probably forms a 2:1 octahedral complex with Cu+2. It has the advantage of being administered orally and is nontoxic with relatively few side effects, based on case studies of patients who have taken this drug daily for decades.

Jones has referred to D-penicillamine as the nearly ideal chelate compared to chelating agents for other metals, which must be given intravenously under supervision by trained medical personnel, require more frequent urine monitoring of essential trace elements, and have more serious side effects.7 Hypersensitivity (such as a rash or an elevated fever) is the most frequent symptom, which usually occurs seven to 10 days after beginning therapy and can be reversed by discontinuing the medication.

Most patients who exhibit such side effects can eventually adapt to D-penicillamine by reinstituting the drug at a very low level and then progressively increasing the dose.22 If the manifested side effects are too severe, trienthine hydrochloride (Trien, triethylenetetramine, Syprine®) becomes the second drug of choice for the treatment of Wilson’s disease. It is a derivative of ethylenediamine, has four amine nitrogen atoms (a tetradentate ligand) available for metal bonding and is marketed in capsule form. No toxic effects have been described for 41 patients using this drug for two to 164 months.24

Mercury is a very toxic element found in different physical forms in the environment, including elemental mercury (Hg0), inorganic mercury salts (Hg+1, Hg+2) and organomercury compounds such as methylmercury (MeHg). Elemental mercury vapor accounts for most occupational exposures.25 Mercurous chloride, also known as calomel, has mercury in the +1 oxidation state and was commonly used in teething powders and other medicines until its adverse effects were publicized in 1948.

Mercuric (Hg+2) salts are used to inhibit bacterial or fungal growth. Methylmercury is most frequently involved in mercury food poisoning. Any mercury compound released into the environment becomes available for subsequent methylation to MeHg by microorganisms found in the soil and streams. MeHg concentrates in predacious fish, such as pike in fresh water, tuna, shark and swordfish in marine water. Levels can reach more than 50 times the average mercury concentration found in most other fish and present a potential risk to the consumer.25

The FDA is responsible for regulating commercial fisheries.

Federal regulations require that marketed fish contain no more than one part per million (ppm) of mercury. Sport fishing is virtually unregulated, however, and presents the highest risk of exposure to the public. Advisories are issued to warn the public if streams and rivers are found to be polluted. Ingestion of fish or grain contaminated with methylmercury resulted in epidemics of neurotoxicity and death in Minamata, Japan, in the 1950s and in Iraq in 1973. In the Minamata Bay epidemic, the cause was traced to the toxic discharge of effluents into the bay from a local manufacturing plant. The plastics facility was using a mercury catalyst to make vinyl chloride.25 This caused 41deaths and at least 30 cases of infantile cerebral palsy. In the Iraqi tragedy, people were poisoned after eating homemade bread prepared from wheat that had been contaminated with a fungicide that contained methylmercury.

In addition to supportive therapy, mercury poisoning is often treated with a chelating agent. BAL was the chelator of choice for severe inorganic mercury poisoning.26 With much of the cellular damage due to mercury combining with protein sulfhydryl groups (-SH), BAL competes with the body’s sulfhydryl groups by forming a –S–Hg–S– linkage to produce a stable five-membered ring structure. Because of the toxicity associated with BAL, newer analogs have been developed that have fewer side effects. DMSA was reported in 1976 to be very effective as an antagonist for mercuric chloride and methylmercury chloride and was later shown to be superior both to BAL and D, L-penicillamine.7

Other reports suggest that while elemental and inorganic mercury can be removed from tissues by chelating agents, it is unlikely that methylmercury can be chelated. The theoretical reasoning being that the methylmercury cation, CH3Hg+, forms a thermodynamically stable bond with the deprotonated thiol group of proteins, effectively precluding metal complexation with both sulfhydryl groups of the chelating agent.27 In fact, BAL is contraindicated for MeHg poisoning because it has been shown to increase the concentration of MeHg in the brain, exacerbating symptoms.25,28,29 Autopsied brains have shown that MeHg had been biotransformed into inorganic mercury, which only poorly crosses the blood-brain barrier.

•Cadmium Chelation

Cadmium bioaccumulates in the food chain and tobacco leaves because of the agricultural use of cadmium-containing fertilizers and soil contaminated by sewage sludge and polluted groundwater.

In 1946, the inhabitants of the Jintzu River basin in Japan were afflicted with a disease (characterized by pain and bone fractures) that was caused by consuming water and rice contaminated with cadmium-containing discharges from a local zinc mining operation.

The disease, which caused severe bone porosity and spontaneous fractures, became known as itai-itai or ouch-ouch disease and afflicted mostly postmenopausal women.30

Occupational exposure to cadmium has been recognized as a significant health hazard and workers are covered by the 1992 OSHA Cadmium Standard. This standard provides for periodic biological monitoring of blood and urine cadmium levels and urine beta-2-microglobulin as a marker of renal tubular damage. However, environmental exposure is much more insidious and potentially poses more of a public health problem than workplace exposure.

Cigarette smoke remains the most significant source of environmental exposure to cadmium.31 Each cigarette contains 2 mcg of cadmium, more than half of which is absorbed from the lungs during active cigarette smoking. Pack-a-day smokers can have blood levels and body burdens twice that of nonsmokers. After 20 pack years of smoking, the renal threshold for tubular damage may be breached in some individuals, leading to chronic renal failure and progressing to end-stage renal disease, requiring weekly hemodialysis treatments.

In a 1990 Agency for Toxic Substances and Disease Registry (ATSDR) case study, it was stated categorically that there was no effective treatment for chronic cadmium toxicity and that chelation therapy had no role in cadmium poisoning.30 Macfarland has remarked, "The cure for chronic cadmium intoxication is prevention."32

Studies have shown that cadmium is tightly bound intracellularly to the protein metallothionein (MT) in liver and kidney, and this complex is gradually mobilized from liver to kidney, which is considered the critical organ for cadmium toxicity. Ironically, although the role of MT is considered to be mostly protective, the cadmiummetallothionein complex is still extremely toxic to the kidney. Cadmium accumulates in the kidney because with a biological half-life of about 30 years, its excretion rate is very slow. The problem is that most chelating agents that do remove cadmium from the liver are filtered by the kidney and are actively reabsorbed by the renal tubular cells, producing nephrotoxicity. The most logical approach, therefore, is to develop a chelating agent cleared by the bile before ever reaching the kidney, or design a chelating agent with high affinity for cadmium that can be filtered easily by the kidney but isnot appreciably reabsorbed.33

Most of the early animal studies on cadmium chelation focused on the use of BAL and EDTA. BAL was successful to some extent, but the mortality rate was high and correlated with the extent of renal failure.33 A BAL-glycoside derivative was found to be more effective than BAL in removing intravenously administered cadmium chloride in the rabbit because less cadmium was deposited in intracellular sites in the kidney.33

Friberg examined the effect of CaNa2EDTA on cadmium intoxication in rats. He found an increase in renal damage in the rats given CdCl2 and CaNa2EDTA together compared with cadmium alone. This study demonstrated that these chelators caused significant renal damage in animals with chronic cadmium intoxication and concluded that chelation therapy is contraindicated.34 Most chelating agents also do not effectively mobilize cadmium from intracellular deposits.

The last decade has seen much progress in the synthesis of new compounds having the properties described above for an effective cadmium chelator. Derivatives of dithiocarbamates have shown promise as safe therapeutic chelating agents that can be used to assess body burden and enhance urinary excretion.

In 1981, Gale et al began publishing their investigations of the therapeutic effects of a series of substituted dithiocarbamates as antagonists for acute cadmium poisoning.35 Sodium diethyldithiocarbamate (DDTC) was effective as a cadmium antagonist but was later shown to increase the cadmium content of the brain.7 Structural changes in the groups attached to the dithiocarbamate moiety were found to reduce or eliminate cadmium brain deposition. The most promising cadmium chelating agent is sodium N-(4-methoxybenzyl)-D-glucamine dithiocarbamate (MeOBGDTC).

Animal experimental models have shown that MeOBGDTC and glutathione are able to complex cadmium and subsequently remove it in the bile; however, its use in humans has not been demonstrated, especially in workers with inhalation exposure from metal fumes, the major route of cadmium exposure in occupational health.

Reports of acute oral cadmium poisoning are less common since cadmium coating of kitchen utensils was prohibited after World War II. Most cases involve spousal poisonings; results can be deadly.

•Iron Chelation

Hereditary hemochromatosis and ß-thalassemia major are two genetic diseases associated with iron overload. In the case of ß-thalassemia major, or Cooley’s anemia, iron overload results from the frequent blood transfusions used to manage associated anemia and suppress expansion of the bone marrow. Left untreated, ß-thalassemia is invariably a fatal disease, with most patients succumbing to congestive heart failure before the age of two. With strict adherence to the hypertransfusion regimen, however, patients can live into their third or fourth decade or longer, provided the iron overload is kept under control.38

The basic defect in ß-thalassemia is the inability to produce the ß-globin chain of hemoglobin, resulting in extreme peripheral anemia and accompanying hypoxia. The blood of affected individuals contains only hemoglobin F, which poorly nourishes the peripheral tissues with oxygen.

In untreated subjects, the bone marrow undergoes uncontrolled expansion in a futile attempt to produce more red cells and the peripheral anemia eventually progresses to death from cardiac failure.

The resulting bone marrow expansion produces enormous hepatosplenomegaly and characteristic bone malformations, known as Cooley’s facies.38 In these transfusion-dependent anemias, the goal is to identify affected patients as early as possible and start transfusion therapy. If transfusion therapy is started early enough to suppress the bone marrow completely, physical defects are avoided and the patient appears completely normal.38

The tradeoff for clinical improvement and normal appearance permitted by hypertransfusion therapy is the excessive accumulation of iron in the internal organs, which may ultimately lead to massive hemosiderosis and death.38 This accumulation results because there is no physiological mechanism for excreting excess iron and, with venesection (therapeutic phlebotomy) not an option, chelation therapy must be initiated to save the lives of these patients.

Left unchecked, transfusional overload usually leads to death from cardiac dysfunction in the second decade of life.

The objective of chelation therapy is to return iron stores to levels unlikely to cause toxicity. Iron stores are best evaluated by liver biopsy, although there is some risk of mortality associated with this procedure.

Normal iron loads in liver are <1 mg/g (dry weight). Mildly increased levels (as seen in patients heterozygous for hereditary hemochromatosis) are 3 mg/g –7 mg/g and do not pose an increased risk for cardiac or hepatic complications. Hepatic iron concentrations of 8 mg/g –15 mg/g carry an increased risk and levels of >15 mg/g are associated with a greatly increased risk of cardiac disease and premature death.39

Every unit of transfused blood adds approximately 180 mg of iron. Assuming that each ß-thalassemia major patient receives on average about 25-30 units of blood a year after the age of 15 years, 4.5 g–5.4 g of iron accumulate yearly. At this rate, by the third decade of life, more than 70 g of iron have been deposited in the internal organs. This is the maximum amount tolerated before the development of serious symptoms that invariably lead to death, primarily from cardiac hemosiderosis.38

Parenteral chelation therapy with deferoxamine mesylate (DFO, Desferal®) has become the standard of care for reducing the body burden of iron in patients with transfusion-dependent anemias.40

Although deferoxamine is water soluble, it is inactive orally because of poor absorption from the gut, making parenteral routes (IV, IM, or IP) of administration necessary.

Deferoxamine is a hexadentate ligand that forms a stable 1:1 octahedral complex with iron by coordinating all six iron-binding sites. DFO chelates iron, derived from plasma macrophages after catabolism of red cells, to form ferrioxamine, which is readily cleared by the kidneys. Iron bound to plasma transferrin is not easily chelated and iron-hemoglobin bonding is not disturbed at all.

Hepatic uptake of deferoxamine results in chelation of cytosolic iron and subsequent biliary excretion into the feces.

The measurement of serum ferritin levels is the simplest way to monitor excessive iron loading, but as an acute-phase protein, ferritin can be falsely elevated due to hepatic inflammation or disease.

To reduce the incidence of iron-induced complications, target ferritin levels should be in the range of 1000 mcg/L –2000 mcg/L and (ideally) should be maintained below 1000 mcg/L. Patients with most serum ferritin concentrations exceeding 2500 mcg/L have an estimated cardiac disease-free 15-year survival of less than 20 percent.40 Studies have shown that patients who comply with a regimen of subcutaneous deferoxamine therapy between 225 to 330 times per year (approximately four to six times per week), have a 92 percent chance of surviving to 30 years of age.

Despite the success encountered with deferoxamine in western countries, the expense and strict regimen required make its use less than ideal in third world countries, where universal health care is often not available and cost is an impediment to patient compliance.

In this regard, a worldwide search has continued for an orally active iron-chelating agent. The one most extensively evaluated is deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one; L1).40,41 Deferiprone is a bidentate molecule and forms a 3:1 octahedral complex with extracellular iron, which is excreted almost exclusively via the kidneys. Stool iron excretion is lower with deferiprone (23 percent of the total iron excreted) as compared with deferoxamine (59 percent of total iron excreted), making deferiprone less efficacious in the short-term.40

In 1995, deferiprone was licensed for sale in India, where there’s a relatively large number of patients with limited access to chelation treatment. The most serious side effect associated with deferiprone is agranulocytosis, a potentially life-threatening condition. Consequently, it is advisable to monitor patients with a weekly white blood cell count. At the first sign of neutropenia, the drug should be stopped.40

In North America, deferiprone is still an experimental drug, as its long-term efficacy and toxicity have not been established. A randomized clinical trial comparing deferiprone with deferoxamine was terminated prematurely by its corporate sponsor, Apotex Pharmaceuticals (Weston, Canada), in 1996 after results showed a 50 percent increase in mean hepatic iron concentration in patients treated with deferiprone.40 There remains a need for carefully controlled randomized clinical trials of other oral iron chelators.

Hereditary hemochromatosis is the most common autosomal recessive disorder found in Caucasians with an incidence of about 1 in 200 (0.5 percent).42 Homozygous individuals are at risk for developing severe and potentially lethal hemochromatosis, characterized by increased absorption of iron from the gut and subsequent deposition in the soft tissues. The long-term effects of iron toxicity are identical to those associated with hypertransfusion treatment for ß-thalassemia.

Iron is a cumulative toxin; it takes years to develop symptoms.

Men rarely display full symptoms prior to age 40 and women before menopause (50 to 60 years of age).36 As is the case for ß-thalassemia, the "gold standard" for the diagnosis of hemochromatosis is liver biopsy for measurement of iron content. Therapeutic phlebotomy is the treatment of choice for iron overload. Chelation is not recommended as a substitute for phlebotomy unless the patient presents with anemia, hypoproteinemia or severe cardiac disease, precluding phlebotomy.42

Deferoxamine remains the treatment of choice for acute iron poisoning. From 1991 to 1993, the annual number of reported medical emergencies involving iron averaged 22,000, with the majority of cases involving accidental ingestion of multivitamin preparations by children younger than six years.43

Of major concern is ingestion of concentrated iron supplements that pose the highest risk of morbidity and mortality. Clinical toxicity is expected following ingestion of iron in excess of 20 mg/kg.43

Emergency room calculations are based on the number of tablets ingested and their weight percentage of iron.

Iron produces direct, localized corrosive effects on intestinal mucosa and can cause mucosal irritation, ulceration, bleeding, ischemia, infarction and perforation. Vomiting, diarrhea and abdominal pain are the classic initial symptoms of iron toxicity. A lactic acidosis usually develops within 24 hours due to hypotension, anemia secondary to gastrointestinal bleeding and tissue hypoperfusion.43

With normal serum iron concentrations of 50 mcg/dL—150 mcg/dL, peak levels (four hours after ingestion) greater than 350 mcg/dL are usually associated with systemic toxicity, although a level less than 350 mcg/dL does not preclude iron toxicity.43

A cautionary note expressed by Mills et al is that acute iron poisoning is basically a clinical diagnosis with laboratory tests only serving a confirmatory role and never to be used alone to determine the need for chelation therapy. Intravenous DFO is recommended for acute iron poisoning and is usually administered during a 24-hour period. The criteria for extended DFO infusions are based on practice guidelines developed by Mills et al.43

• Aluminum Chelation

Aluminum is a nonessential element excreted almost exclusively by the kidneys. In patients with end-stage renal disease (ESRD) undergoing dialysis treatment, aluminum can accumulate in tissues, with brain and bone being the target organs for aluminum toxicity. Dialysis encephalopathy syndrome (DES), characterized by mental deterioration, focal neuropathy, convulsions and death, is primarily an iatrogenic disease resulting from prolonged exposure to aluminum-containing dialysis solutions. Serum aluminum levels are typically 100 mcg/L -200 mcg/L (normal: <10 mcg/L) in these 8 patients. Fortunately, the use of aluminum-free water for dialysis has largely eliminated DES.

Patients must still limit their intake of aluminum-containing medications, including antacids. The use of blood replacement products, particularly those in which citrate is used as the anticoagulant, will elevate serum aluminum levels in renal impaired patients.44

Dialysis is not able to remove significant amounts of aluminum from blood so that some buildup invariably occurs. Patients with sustained serum aluminum levels >60 mcg/L are at risk for developing dialysis dementia, microcytic anemia, osteodystrophy and osteomalacia secondary to aluminum exposure.

The diagnosis of aluminum-related osteodystrophy has been made using the deferoxamine infusion test.45 Baseline serum aluminum concentrations of >200 mcg/L are highly specific for this disease (specificity, 93 percent) but have a sensitivity of only 43 percent.

After administration of deferoxamine, an incremental increase

of 200 mcg/L above the baseline value identified 35 of 37 patients

with aluminum-related osteodystrophy (sensitivity, 94

percent; specificity, 50 percent).45

Primary prevention is aimed at identifying and controlling potential

sources of exposure before decorporation is initiated.

Decorporation, which is the process of removing aluminum from

the body, may be achieved using chelators. Aluminum exists as a

trivalent cation in solution and is 90 percent bound to transferrin

in plasma; however, the affinity of transferrrin for aluminum is 10

orders of magnitude less than it is for iron.46 Consequently, aluminum

does not displace or interfere with iron binding to transferrin

and may help account for the affinity of iron chelators for aluminum.

Al+3 has a preferred coordination number of six, similar to

iron.

On the other hand, iron complexes are more stable than aluminum

complexes due to overlap of functional group donor oxygen

or nitrogen p-orbital electrons with iron 3d-orbitals. As Yokel

et al have pointed out, it may not be possible to design a chelator

that has greater affinity for aluminum than for iron.47

In 1995, Anthone et al used a hollow-fiber extracorporeal device

containing immobilized deferoxamine (DFO), connected in series

with the dialyzer, to augment aluminum removal from the blood.

This eliminated any DFO-related patient side effects. Its long-term

safety and efficacy compared to parenteral DFO is being

evaluated.48

Deferoxamine has been used as an aluminum chelator since

1980, although it is not FDA-approved for this indication; however,

chelation with DFO is considered first-line therapy for aluminum

accumulation in patients with ESRD. There does not appear

to be any significant iron depletion in these patients as a result

of chelation therapy.

Within 24 hours of treatment, the DFO-Al complex peaks in

plasma and can be cleared by dialysis. Patients with DES improve

clinically with chelation therapy, as do patients with

symptoms of dialysis osteomalacia. Since DFO is not an ideal

chelator, particularly for long-term prevention or treatment of

aluminum accumulation, the search for alternative orally active

medications continues.

In the industrial setting, aluminum toxicity is primarily due to

chronic respiratory exposure. Inhalation of aluminum-containing

fine dust particulates can occur in poorly ventilated work spaces.

Pulmonary fibrosis has been reported in workers exposed to fine

aluminum dust. Bauxite, the only major commercial source of aluminum,

is composed of 45 percent to 60 percent aluminum oxide

(alumina). Mining of this ore by workers can be hazardous without

proper respiratory protection.

concerns the possible beneficial effects of removing toxic

metals in asymptomatic individuals having merely low-level environmental

reports that toxic effects due to lead, cadmium and mercury exposures

may occur at levels previously thought to be safe.

Goyer, who serves as a scientific advisor to the director of the National

Institute of Environmental Health Sciences, has stated, "It is

clear that the margin between the levels of exposure for persons living

in the industrialized nations of the world and levels of exposure

currently recognized as producing the lowest adverse effect is

cognitive and behavioral development in children, progressive

accumulation of cadmium in liver and kidney associated with

renal tubular dysfunction and hypercalciuria in later life, and allegations

that mercury vapor released from dental amalgam may be

science-based and have randomized clinical trials data to

support their claims. Several off-label uses for approved drugs

appear to be beneficial for reducing body burdens of other

for the treatment of acute iron intoxication and also used to

chelate aluminum in overload situations.

Genetic diseases, such as ß-thalassemia, would exhibit much

higher morbidity and mortality without chelation therapy used as

an adjunct or as primary treatment.

Environmental exposure to lead still presents a major health risk

for children, especially those in lower socioeconomic groups. In the

first two years of life, children are extremely susceptible to the deleterious

effects of lead on neurological development. State screening

programs and agencies have been effective at identifying children

with elevated BLL and following up with the appropriate medical

treatment and, if necessary, providing for lead remediation of older

homes found to be the source of lead exposure. In this context,

chelation therapy becomes a medical emergency for treating children

with BLL >45 mcg/dL. Occupational exposures to lead and

cadmium are covered by OSHA standards. State health departments

are leading initiatives to lower the action levels to reflect current

medical practices.

The search for newer and more effective (specific) chelators, including

the work of Dr. Mark Jones at Vanderbilt University, continues

at research institutions throughout the country. Unfortunately,

funding for basic research in this field is often limited.

Moreover, there is not a stream of chelation drugs in the pipeline.

The federal government must subsidize research and development

for these so-called "orphan" drugs as major pharmaceutical companies

are typically not interested in this market because of the small

return on investment. This situation probably will not change unless

some revolutionary medical discovery or breakthrough comes

about. Without foundation grants to support ongoing clinical investigation,

1995;103(11):988-989.

NJ: Medical Economics Company; 2000:1660-1661.

4. Chisolm JJ Jr. BAL, EDTA, DMSA, and DMPS in the treatment of lead poisoning

1992;30:529-547.

6. Chisolm JJ. The use of chelating agents in the treatment of acute and chronic

7. Jones MM. New developments in therapeutic chelating agents as antidotes for

for Disease Control and Prevention, 1991.

1998;12:499-510.

646S-650S.

1994;125:233-234.

13. Hipkins KL, Materna BL, Kosnett MJ, Rogge JW, Cone JE. Medical surveillance

14. Occupational Safety and Health Administration (US Department of Labor).

Employee standard summary. (1910.1025 App B) Washington, DC: Occupational

Safety and Health Administration; 1979. Effective: 1March 1979.

15. Porru S, Alessio L. The use of chelating agents in occupational lead poisoning.

16. Occupational Safety and Health Administration (US Department of Labor).

Medical Surveillance Guidelines–1926.62 App C.

17. Kaufman JD, Burt J, Silverstein B. Occupational lead poisoning: Can it be

1998;57:719-726.

19. Lin JL, Ho HH, Yu CC. Chelation therapy for patients with elevated body

20. McDonald LV, Lake CR. Psychosis in an adolescent patient with Wilson’s disease:

22. Shimizu N, Yamaguchi Y, Aoki T. Treatment and management of Wilson’s

NJ: Medical Economics Company; 2000:1776-1778.

NJ: Medical Economics Company; 2000:1887-1888.

25. Agency for Toxic Substances and Disease Registry (US Department of

for Disease Control and Prevention, 1992.

26. Singer AJ, Mofenson JC, Caraccio TR, Ilasi J. Mercuric chloride poisoning

27. Goyer RA, Cherian MG, Jones MM, Reigart JR. Role of chelating agents for

28. Davis LE, Kornfeld M, Mooney, HS, et al. Methylmercury poisoning:

Long-term clinical, radiological, toxicological, and pathological studies of an affected

29. Nierenberg DW, Nordgren RE, Chang MB, et al. Delayed cerebellar disease

1998;338:1672-1676.

30. Agency for Toxic Substances and Disease Registry (US Department of

Centers for Disease Control and Prevention, 1990.

33. Jones MM, Cherian MG. The search for chelate antagonists for chronic cadmium

35. Gale GR, Smith AB, Walker EM. Diethyldithiocarbamate in treatment

36. Andersen O. Oral cadmium exposure in mice: Toxicokinetics and efficiency

37. Jones MM, Singh PK, Basinger MA, Gale GR, Smith AB, Harris, WR.

Design of in vivo cadmium-mobilizing agents: synthesis and properties of

373.

38. Piomelli, S. The management of patients with Cooley’s anemia: Transfusions

1997;17:407-421.

40. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment

158.

42. Walker EM, Wolfe MD, Norton ML, Walker SM, Jones MM. Hereditary

1994; 12:397-413.

44. Yokel RA, Ackrill P, Burgess E, Savory J, et al. Prevention and treatment

45. Milliner DS, Nebeker HG, Ott SM, Andress DL, et al. Use of the deferoxamine

infusion test in the diagnosis of aluminum-related osteodystrophy.

46. Abreo K, Glass J. Cellular, biochemical, and molecular mechanisms of

47. Yokel RA. Aluminum chelation: chemistry, clinical, and experimental

48. Anthone S, Ambrus CM, Kohli R, Min I, et al. Treatment of aluminum

1995;6:1271-1277.

After reading the article, complete the CME/CE Registration

and Answer Form and answer the self-assessment

and evaluation questions. Send your completed

CME/CE Registration and Answer Form along

with the $10 fee to the Office of CME. Continuing education

credit will be awarded to those participants

achieving a score of 70 percent or higher.

a. square planar

b. tetrahedral

c. octahedral

d. trigonal biplanar

e. cis, trans isomer

a. CaNa2EDTA.

b. DMSA.

c. BAL.

d. deferoxamine.

e. both a and b.

a. 10 mcg/dL.

b. 25 mcg/dL.

c. 40 mcg/dL.

d. 50 mcg/dL.

e. 60 mcg/dL.

a. 120.

b. 150.

c. 180.

d. 210.

e. 240.

a. D-penicillamine.

b. BAL.

c. DMSA.

d. CaNa2EDTA.

e. none of the above.

a. the cadmium-chelate is excreted into

the bile.

b. cadmium is not displaced from

metallothionein.

c. CaNa2EDTA must be taken orally.

d. the resulting complex is actively reabsorbed

by the renal tubules, producing

nephrotoxicity.

e. most chelating agents act intracellularly

by diffusing across cell membranes.

a. >350, <400

b. >400, <450

c. >450, <500

d. >500, <550

e. None of the above

a. No.

b. Insufficient data to make judgment.

c. Yes.

d. Yes, but this does not constitute a medical

emergency.

e. No, patient should be sent home with no

follow-up.

a. inconclusive.

b. diagnostic.

c. highly consistent.

d. negative.

e. none of the above.

A. Strongly agree

B. Agree

C. Uncertain

D. Disagree

E. Strongly disagree

A. Strongly agree

B. Agree

C. Uncertain

D. Disagree

E. Strongly disagree

A. Strongly agree

B. Agree

C. Uncertain

D. Disagree

E. Strongly disagree

A. Strongly agree

B. Agree

C. Uncertain

D. Disagree

E. Strongly disagree

A. Strongly agree

B. Agree

C. Uncertain

D. Disagree

E. Strongly disagree

A. Strongly agree

B. Agree

C. Uncertain

D. Disagree

E. Strongly disagree

A. Strongly agree

B. Agree

C. Uncertain

D. Disagree

E. Strongly disagree

A. Strongly agree

B. Agree

C. Uncertain

D. Disagree

E. Strongly disagree

A. Strongly agree

B. Agree

C. Uncertain

D. Disagree

E. Strongly disagree

A. Strongly agree

B. Agree

C. Uncertain

D. Disagree

E. Strongly disagree

Comments:

Learning Scope 2 Questions

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