Dimercaprol

Abstract

Treatment of mercury toxicity is controversial and not well studied. Currently there are several proposed methods of chelation and subsequent removal of mercury from the body, including dimercaptopropanesulfonate, dimercaptosuccinic acid, intravenous vitamin C and edetate. Although many of these methods are not approved by the US Food and Drug Administration, they are being used with modest success. Because of the lack of information regarding treatment outcomes, Medical-Dental Pharmacy performed a retrospective analysis of 28 randomly selected patients for whom we had supplied dimercaptopropanesulfonate in the last 6 months. Dimercaptopropanesulfonate is used to treat mercury toxicity and as provocation to perform mercury testing. Two of the 28 selected patients who received the prescription decided against treatment. Of the remaining 26 patients, 8 patients were using dimercaptopropanesulfonate for treatment with varying success. Overall, this retrospective study shows that dimercaptopropanesulfonate is a safe and effective agent to use for initial mercury level testing.

Introduction

Mercury has no known function in the human body and can cause a host of problems. It is found in both organic and inorganic forms and can be toxic in any form. Organic mercury is more toxic, as it can permeate membranes and may accumulate in the brain.1 Mercury also binds to the sulfur in thiol groups in the body, which interferes with protein formation and a variety of enzyme reactions.1 The most common source of mercury toxicity is amalgam dental fillings, which millions of people possess.1,2 The mercury in the fillings interacts with saliva to produce a toxic vapor, which is slowly inhaled over the years. In addition, constant wear breaks off minute pieces of amalgam, which are ingested.1 Normal bacterial flora converts the inorganic mercury in amalgam to methyl mercury, an organic form of mercury.1 Mercury toxicity may manifest as vague symptoms, ranging from fatigue, weakness, headache and anxiety to skin irritations and digestive disorders (Doctor's Data Inc., Chicago, Illinois, laboratory report, unpublished data).1 To correct or reverse mercury toxicity, it is imperative to remove the mercury.

The main objective of mercury chelation therapy is to achieve mercury levels of less than 3 pg/g creatinine. Mercury attaches itself to the sulfur in dimercaptopropanesulfonate (DMPS), which forms a mercury-DMPS complex that is removed by renal excretion.3 It is believed that excretion occurs through the organic anion transporter 1 in the basolateral membrane of the proximal tubule.3 An estimated 3.8 to 21 pg of mercury leaks from amalgam fillings per day, and DMPS therapy may remove up to 1 mg of mercury per day.1,4 Listed below are some of the common side effects reported for dimercaprol, the parent drug of DMPS:5

* Agitation

* Burning sensation of mouth, throat and eyes

* Chest constriction

* Headache

* Nausea

* Tachycardia

* Tingling of extremities

* Vomiting

Materials and Methods

Pharmacy records were reviewed to identify patients who had received prescriptions for DMPS from June 1, 2002, to December 23, 2002. Records identified 113 prescriptions, but 16 of these prescriptions were eliminated because they were from physicians who had not been contacted tor permission to review patient charts. From the pharmacy's records, 28 patients were randomly selected from the remaining patients. Of these remaining patients, four were eliminated because they were physicians or part of the examining doctor's staff. Six patients who had their amalgams removed prior to our study also were eliminated.

DMPS was prepared by use of dimercaptopropane sulfonic acid (Lot 101297, Medisca, Inc., New York City, New York); no excipient was used, and the capsules were made in No. 1, 0 or 00 size capsules, depending on the dose and weight.

Dimercaptosuccinic acid (DMSA) capsules were made by the same method as the DMPS capsules with no excipients added and placed in No. 3, 1, or 0 size capsules, depending on the dose and weight.

Edetate (EDTA), given by intravenous (IV) infusion, was prepared (formulation is provided with this article) using EDTA disodium powder 150 mg/niL in sterile water for injection (Lot 01-581-48-1, Abbott Laboratories, Montreal, Canada) with the pH adjusted to 9 using 10% sodium hydroxide freshly prepared in sterile water for injection (Lot 01-581-48-1, Abbott Laboratories). The solution was bottled in presterilized amber 50-mL vials that were sealed and autoclaved at 121°C for 25 minutes. An electronic balance (Model XL-410-D, Denver Instrument, Denver, Colorado) with a readability of 0.001 g was used in weighing the drug.

Each patient's dosage of DMPS was determined at 4.9 mg to 5 mg/kg of patient weight. A provocation dose was given immediately after the initial morning bladder voiding, one single dose was taken, and urine was collected for 6 hours. The urine sample was analyzed for mercury content by Doctor's Data, Inc.; and patients determined to be high in mercury were given oral doses of DMPS, DMSA or EDTA, or IV vitamin C. Those given DMPS therapy were given the same dose as the original challenge, once a week for 5 weeks, and another urine sample was collected in the sixth week without drug. This sample was also analyzed for mercury content.

A review was performed at the doctor's office to obtain the following patient information:

* Age

* DMPS orders (or other means ot treatment)

* DMPS side effects

* Liver function (if information available)

* Mercury testing results

* Weight

After reviewing the medical charts, we re-evaluated the pharmacy records to verify whether DMPS prescriptions reflected courses of treatment or provocation tests. Patients who had received DMPS were interviewed regarding side effects and satisfaction. Results of the evaluations are compiled in Table 1.

Results

This retrospective study revealed that after initial testing five patients had toxic mercury levels less than 3 µg/g creatinine, two patients had toxic levels between 3 and 6 µg/g creatinine, and 19 patients had toxic levels of greater than 6 µg/g creatinine. Eight patients received treatment with DMPS, and after 5 weeks of treatment seven of those eight patients had decreased mercury levels; one patient experienced an increase. Four patients received an additional 5 weeks of treatment. During the second course of therapy, three of the four patients treated tested with a lower level of mercury (above 6 µg/g creatinine), and one of the four patients tested with a higher level of mercury. Three patients who received a second cycle of treatment also received a third cycle. Of these three patients, two experienced an increase in mercury level, and one a decrease (a mercury level above 6 µg/g creatinine).

Conclusion

DMPS is an extracellular chelating agent that was first developed in China. It has a high affinity for mercury, copper and zinc. Once mercury-containing amalgam has been removed, DMPS is used as a challenge test to determine whether or not the patient carries a greater than desirable mercury load.

Of the 26 patients, 23 had detectable urine levels after the DMPS challenge. Interpretation of post-treatment urine tests is difficult because the level of mercury reflected in the urine represents the amount excreted after a single dose of DMPS. Since DMPS remains intracellular, a patient might have a significantly lower total body mercury burden after a series of DMPS treatments, but that same patient may have an elevated value in the follow-up urine test. This reflects that there was likely more intracellular mercury available to be chelated and excreted into the urine after the single follow-up dose of DMPS.6

The patients involved in the study exhibited few side effects from DMPS. A few patients complained of nausea or an upset stomach, side effects that appeared to diminish by giving the dose with food. One patient experienced numbness, tingling and burning in the legs, and swelling of the hands, face and ankles; the reaction was considered serious enough to discontinue treatment. Another patient reported swollen lips and a rash but elected to continue treatment. A third patient complained of increased tiredness. It is difficult to differentiate between possible side effects, such as burning, tingling and swelling, and more serious hypersensitivity reactions; therefore, if serious side effects occur, treatment should be discontinued.

Overall, this retrospective study shows that DMPS is a safe and effective agent to use for initial mercury level testing.

METHOD OF PREPARATION

Note: This preparation should be prepared in a laminar airflow hood in a cleanroom or via isolation barrier technology by a validated aseptic compounding pharmacist using strict aseptic technique.

1. Calculate the quantity of each ingredient for the total amount to be prepared.

2. Dissolve the edetate disodium and benzyl alcohol in approximately 90 mL of sterile water for injection.

3. Adjust the pH to about 9, at which point the solution will be clear.

4. Add sufficient sterile water for injection to volume and mix well.

5. Filter through an appropriate sterile 0.2-µm filter into sterile containers.

6. Package and label.

References

1. [No author listed.] The New Zealand Health Network. Mercury Chelation. Available at: www.nzhealth.hvpermart.net/poisons/mercury2.html. Accessed December 21, 2002.

2. HoI PJ, Vamnes JS, Gjerdet NR et al. Dental amalgam affects urinary selenium excretion. Biol Trace Elem Res2002; 85(2): 137-147.

3. Koh AS, Simmons-Willis TA, Pritchard JB et al. Identification of a mechanism by which the methylmercury antidotes N-acetylcysteine and dimercaptopropanesulfonate enhance urinary metal excretion: Transport by the renal organic anion transporter-1. MoI Pharmacol 2002; 62(4): 921-926.

4. Winker R, Schaffer AW, Konnaris C et al. Health consequences of an intravenous injection of metallic mercury. IntArch Occup Environ Health 2002; 75(8): 581-586.

5. [No author listed.] Dimercaprol. Available at: www.inchem.org/documents/ pims/pharm/dimercap.htm. Accessed December 21, 2002.

6. Rozema TC. The protocol for the safe and effective administration of EDTA and other chelating agents for vascular disease, degenerative disease, and metal toxicity. J of Adv Med 1997; 10:5-100.

Barry Smith, PharmD * Patrick Golden, MD * Carrie Pingree

Medical-Dental Pharmacy

Fresno, California

Address correspondence to: Bany Smith, PharmD, Medical-Dental Pharmacy, 689 E. Nees, Fresno, CA 93720. E-mail: mdpii@aol.com

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