Project Identifier: ORAU-78-96
Project Title:
Use of Ca-DTPA and Zn-DTPA for Chelation Therapy of Heavy Metals (FDA IND 4041 and 14,603)
Principle Investigator:
Dr. Robert C. Ricks
Principle Investigator's Institution: Oak Ridge Associated Universities
Project started in: 1978
Project Funding Information:
Project received funding in Fiscal Year 1995.
Project used human subjects in Fiscal Year 1995.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: August 05, 1995
IRB Approval Number: 96
Number of Human Subjects in the Last Reporting Period for this Project: 7
(Reporting periods vary.)
Type of Human Subjects Involvement:
Therapeutic parmacological agent.
IND 4041, Trisodium calcium diethylenetriaminepentaacetate (Ca-DTPA) and IND 14603, Trisodium zinc diethylenetriaminepentaacetate (Zn-DTPA) are investigational new drug (IND) applications which are administered by Oak Ridge Associated Universities under contract with the U.S. Department of Energy, Contract No. DE-AC05-76OR00033. Both forms of DTPA have been widely used in the U.S. and in Europe for many years as chelating agents (agents that bind with radioactive substances and are then excreted) following exposure to plutonium and other heavy elements such as americium, californium, and curium.
Ca-DTPA is approximately 10 times more effective than Zn-DTPA for the initial chelation of transuranic elements. Therefore, Ca-DTPA should be used whenever larger body burdens of transuranics are involved. Ca-DTPA is the drug of choice for initial patient management of internal contamination with transuranic elements unless contraindicated. After approximately 24 hours, however, Zn-DTPA is, for all practical purposes, as effective as Ca-DTPA. This comparable efficacy, coupled with its lesser toxicity, makes Zn-DTPA the preferred agent for protracted therapy. The effectiveness of chelation therapy is highly dependent not only on the metal itself, but also on the chemical and physical characteristics of the compound at the time of DTPA administration. Because the efficiency of chelation decreases with time, DTPA should be given within 6 hours of exposure.
Personally identifiable bodily materials (blood and urine samples) are collected to establish pre-treatment base-line levels (blood cell counts, blood and urine nitrogen, serum creatinine, urinalysis, and urine radioassay). During and following treatment, personally identifiable bodily data are collected for clearance rate determination (urine and fecal samples for bioassay and blood assays).
No serious toxicity in human subjects has been reported as a result of over 600 Ca-DTPA administrations in recommended doses. In addition, no serious adverse effects have been noted as a result of over 1000 doses of Zn-DTPA in the recommended dosage. When given repeatedly, with short intervals for recovery, Ca-DTPA and Zn-DTPA treatment may both cause nausea, vomiting, diarrhea, chills, fever, pruritus, and muscle cramps in the first 24 hours. The rate of adverse effects, mostly minor as noted above, is approximately 2.7%. Anosmia (loss of the sense of smell) was observed in one individual after 123 g of Ca-DTPA over twenty-seven months of therapy and possibly could have been related to zinc depletion. After 100 days of no further DTPA administration, the patient's sense of smell began to return. In one patient, long-term, low-dose combination Ca/Zn-DTPA administration was begun using the following schedules: 1 g Ca-DTPA q 24 hr, 1 g Ca-DTPA q 12 hr, 1 g Zn-DTPA q 12 hr, 1 g Zn-DTPA q 8 hr, 1 g Zn-DTPA q 12 hr, 0.5 g Zn-DTPA q 12 hr, 1 g Zn-DTPA q 24 hr, and finally 1 g Zn-DTPA three times a week. After 934 days of such administration, no adverse effects were noted.
The chelating efficacy of both Ca-DTPA and Zn-DTPA is greatest when administered immediately or within one hour of exposure when the radionuclide is circulating in or available to the tissue fluids and plasma. However, a post-exposure interval greater than 1 hour does not preclude the administration and effective action of Ca-DTPA. It is a general guide for DTPA therapy that treatment must be specifically tailored for individual patients under the medical judgment of the treating physician. Ca-DTPA and Zn-DTPA generally can be thought of as two components of transuranic decorporation therapy. If there is any contraindication to the use of Ca-DTPA, the same dose of Zn-DTPA may be substituted. We continue to monitor the use of Ca-DTPA and Zn-DTPA and the incidence of adverse reactions through the REAC/TS DTPA registry. Note: This project combines several projects in the 1994 database: ORAU 47,52,55,64.