METALS IN MEDICINE AND THE ENVIRONMENT

Rheumatoid arthritis is a chronic inflammatory autoimmune disorder that affects one to two percent of people worldwide, and five percent of women over the age of 55 (1).  Women between the ages of forty and sixty are most susceptible to the disease.  It is a painful, incurable disease, and can lead to total loss of joint use within ten years of onset (2).  Symptoms are pain and swelling of the affected joint, and over time the soft tissue surrounding the joint erodes away.  People with advanced rheumatoid arthritis often have deformed hands or feet due to uncontrollable hyperextention or hyperflexation.  The causes of rheumatoid arthritis are unknown. 

joint erosion

Joint Erosion

Two classes of drugs are used to treat rheumatoid arthritis.  The first class of drugs, called “first-line” drugs, are non-steroidal anti-inflammatory drugs (NSAIDs), which include drugs such as aspirin and ibuprofen.  These drugs simply alleviate pain and swelling.  The second class of drugs, or the “second-line” drugs, are disease-modifying anti-rheumatic drugs (DMARDs), and include such drugs as methotrexate, D-penicillamine and various gold salts (3).  DMARDs “modify” rheumatoid arthritis, and are able to slow its advance, allowing patients to retain flexibility and motion for longer periods of time.  In general, these are dangerous drugs and are only prescribed for patients with severe rheumatoid arthritis who are not responding to other treatments.

rheumatoid arthritis hand

Rheumatoid Arthritis Hand

Gold salts have been used to treat rheumatoid arthritis since the early twentieth century.  They are immunosuppressants.  Unlike other DMARDs, gold salts have been known to reverse erosive damage (4).  Examples of gold salts are gold sodium thiomalate (“Myocrisin”), gold thioglucose (“Solganal”) and gold thiosulfate.  Gold sodium thiomalate is the only gold salt that is FDA approved.  Countries outside the United States use other gold salts as well.

The Immune System

Rheumatoid arthritis patients are interested in anything that reduces pain and swelling.  The fact that gold salts are also able to reverse erosive damage makes them especially attractive as a treatment option.

The one biochemical reaction that gold ion is known to have in the body is binding to sulfhydryl groups (-SH) and interfering with reactions that rely on these functional groups (5,6).  This gives gold salts the potential to affect a wide range of reactions.  Links have been found between gold salt therapy and reduced activity of certain areas of the immune system.  For instance, gold salts inhibit the activity of lysosomal enzymes, which are important for the action of phagocytotic cells (7).  In the immune response, infected cells are targeted and attacked by phagocytotic cells, which engulf the infected cells and digest them using lysosomal enzymes.  In another example, studies have found that patients with inflammatory autoimmune disorders have greater levels of “substance P,” a neuropeptide found around nerve cells.  Gold therapy reduces levels of substance P in the blood serum (8).  Several studies have found that gold therapy affects relative levels of prostaglandins (PGs) and leukotrienes.  Specifically, gold salts lower levels of PGF-2α and increases levels PGE2.  PGF-2α is involved in stimulating the release of lysosomal enzymes, while PGE2 inhibits lysosomal enzyme release (9).  By changing relative levels of these prostaglandins, gold salts affect the immune response.

side effects

In short, gold salts suppress the immune response in such a way that the effects of rheumatoid arthritis are greatly reduced and in some cases reversed, making them very attractive to patients.

Mitochondria and Oxidative Stress

Doctors want to prescribe medicine that will treat their patients as well as possible, as fast as possible and as safely as possible.  Gold therapy has the potential to lead to some serious side effects that make doctors leery to prescribe gold salts.

The ability of gold ion to bind to a thiol group allows it to bind to proteins in the mitochondrial membrane.  When this happens, the mitochondrial membrane becomes more permeable to positively charged ions.  This results in decoupling of the oxidative phosphorylation reaction that synthesizes adenosine triphosphate (ATP) (10).  Mitochondria rely on a charge gradient to catalyze ATP production, and when this gradient is disrupted, ATP synthesis is severely inhibited and leads to cell death.  In addition, studies have found that gold may be retained in mitochondria of liver, kidney and bone marrow cells, all areas where gold treatment are the most devastating (11).  The presence of any heavy metal in the liver or kidneys interferes with their filtration function, and can lead to damage that is shown by the secretion of proteins or blood in the urine.  The effect of gold on bone marrow and blood cells (blood cells originate in the bone marrow) are the most serious side effect of gold therapy.  Patients on gold therapy have lower levels of red blood cells, white blood cells and blood platelet cells.  In severe cases, aplastic anemia can occur, where normal bone marrow stem cells are being replaced by fat cells, and the body is physically unable to replenish the blood cells that it is losing (12).  If left untreated, this can lead to death.

oxidative decoupling

Oxidative Decoupling

Thus, while gold salts may have some very beneficial treatment effects, their side effects are common enough and serious enough that doctors shy away from prescribing them.

Drug Comparision

In recent years, gold salts have largely been replaced by other drugs for rheumatoid arthritis treatment, especially the anti-cancer drug methotrexate.  Methotrexate may not be a “better” treatment so much as it is a newer treatment whose track record is not long enough to be as bad as that of gold salts. 

In terms of dosage and effect, methotrexate has an advantage over gold sodium thiomalate.  Methotrexate dosage is 7.5 mg per week, and improvement may be seen in three to six weeks (13).  Gold sodium thiomalate, on the other hand, has a dosage between 25 and 50 mg per week and it may take three to six months for improvement to be detected (14).  In addition, the half-life of gold in the body (3-27 days) is much longer than that of methotrexate (3-10 hours).  So less methotrexate is required for a faster response with less of a chance to cause adverse reactions than gold salts.

Where methotrexate loses out is in side effects and drug interactions.  Overall, methotrexate has fewer side effects than gold salts, and a lower percentage of patients are affected by these side effects.  However, where gold salt side effects are almost always completely reversible upon cessation of treatment, methotrexate side effects, especially lung and liver damage, are not and can cause health problems later. Also, methotrexate interacts with a wide range of other drugs, including NSAIDs used to treat pain, and cause unexpected adverse reactions.  It is never used in conjunction with other drugs.  Gold sodium thiomalate, however, interacts with very few drugs, the most dangerous being penicillamine, another DMARD.  It is always used as part of a drug regime.  Finally, on a more economic basis, gold sodium thiomalate is much cheaper than methotrexate, costing less than $50 for a solution of 10mg/mL (15).  Methotrexate costs between $200 and $300 for 10 mg (16).

drug interactions

Whether or not methotrexate or gold salts are better rheumatoid arthritis drugs is a decision that should be left up to experts; yet looking at the data available to the public, it is not obvious why methotrexate, which appears to be as dangerous a drug as most gold salts, is FDA-approved while most gold salts are not.  It is especially important to note that the mechanism of action in rheumatoid arthritis is unknown for both drugs.  Some patients might prefer to be more at risk for coming down with side effects if those side effects are completely reversible as they are with gold salts.  Doctors want safety and results and  methotrexate gives faster results with fewer side effects.  All drugs containing heavy metals are toxic due to the effects of heavy metals on the body.  They are all dangerous, yet if used correctly and with caution can have great benefit.  Gold salts for treatment of rheumatoid arthritis is a good example of how heavy metal drugs can be taken off the market for being dangerous while other equally dangerous drugs are left on for reasons that are not clear to the public.  Ultimately, while people with little knowledge of medicine should not necessarily have a hand in drug policy, it is important that they have access to information concerning treatment and drug options, and why one treatment is FDA-approved while another is not.

Resources

http://www.medicinenet.com

http://www.hopkins-arthritis.org

http://www.fda.gov

References

(1) Rheumatoid arthritis John Hopkins Arthritis Center.  Accessed November 19, 2007.

(2) “Rheumatoid Arthritis.”  Wikipedia.org.  Accessed November 1, 2007.

(3)  Rheumatoid arthritis MedicineNet.  Accessed November 19, 2007.

(4) Ward, J. R.  Role of Disease-Modifying Antirheumatic Drugs versus Cytotoxic Agents in the Therapy of Rheumatoid Arthritis.  The Amer. J. Med.  (1988) 85, 39-44.

(5) Westwick, W. J., Allsop, J. Watts, R. W. E.  The Effect of Gold Salts on the Biosynthesis of Uridine Nucleotides in Human Granulocytes.  Biochem. Pharmoc.  (1974) 23, 153-162.

(6) Abou-Khalil, W. H, Yunis, A. A., Abou-Khalil, S.  Discriminatory Effects of Gold Compounds and Carriers on Mitochondria Isolated from Different Tissues.  Biochem. Parmoc.  (1981) 30, 3181-3186.

(7) Westwick, W. J., Allsop, J. Watts, R. W. E.  The Effect of Gold Salts on the Biosynthesis of Uridine Nucleotides in Human Granulocytes.  Biochem. Pharmoc.  (1974) 23, 153-162.

(8) deMiguel, E., Arnalich, F., Tato, E., Vaszquez, J. J., Gijon-Banos, J., Hernanz, A.  The Effect of Gold Salts on Substance P Levels in Rheumatoid Arthritis.  Neurosci. Letters.  (1994) 174, 185-187.

(9) Stone, K. J., Mather, S. J., Gibson, P. P.  Selective Inhibition of Prostaglandin Biosynthesis by Gold Salts and Phenylbutazone.  Prostaglandins.  (1975) 10, 241-251.

(10) Abou-Khalil, W. H, Yunis, A. A., Abou-Khalil, S.  Discriminatory Effects of Gold Compounds and Carriers on Mitochondria Isolated from Different Tissues.  Biochem. Parmoc.  (1981) 30, 3181-3186.

(11) Abou-Khalil, W. H, Yunis, A. A., Abou-Khalil, S.  Discriminatory Effects of Gold Compounds and Carriers on Mitochondria Isolated from Different Tissues.  Biochem. Parmoc.  (1981) 30, 3181-3186.

(12) Rawson, N. S. B., Harding, S. R., Malcolm, E., Lueck, L.  Hospitalizations for Aplastic Anemia and Agranulocytosis in Saskatchewan:  Incidence and Associations with Antecedent Prescription Drug Use.  J. Clin. Epidem.  (1998) 51, 1343-1355.

(13) Methotrexate on drugs.com Accessed November 24, 2007.

(14)  Gold sodium thiomalate Accessed November 24, 2007.

(15) Gold sodium thiomalate Accessed November 25, 2007.

(16) Methotrexate Accessed November 25, 2007.

Image source

"Oxidative decoupling" from Voet, Donald; Voet, Judith G.; Pratt, Charlotte W. Fundamentals of Biochemistry; Life at the Molecular Level. Ch. 17:
Electron Transport and Oxidative Phosphorylation. Figure 17-20. John
Wiley & Sons, Inc. 2nd ed. 2006. p. 568.

Author: Megan Love Huffman