Document n4wK2jzB3w37Qdo8oMwpq6Ez

THE USE OF Ca EDTA IN'CASES OF LEAD INTOXICATION In response to the considerable interest which has been expressed in calcium ethylenediaminetetracetate (Ca EDTA), a new drug which shows promise in the treatment of heavy metal poisoning, we are suggesting a protocol for the use of the drug in lead intoxication. The purpose of suggesting a uniform mode of treating cases with this drug is to promote the use of case material as efficiently as possible in gathering information about the drug. It is hoped that during these initial stages the trial of the drug will be limited to experienced clinical investigators with adequate facilities for obser vation and follow up of the patients. As an aid to such investigators, we have summarized the experience in the use of the drug in humans to date and are indicating a dosage schedule based on toxicity studies in animals. These studies were carried out by Dr. George Liaison, Dept, of Pharmacology, Boston University School of Medicine. Mr. Manfred Bowditch, Director of Health and Safety of the Lead Industries Association, has agreed to hold a registry of such protocols of Ca EDTA treated cases of lead poisoning in his office at U20 Lexington Avenue, New York 17, N. Y* It is planned by this means to make the infor mation collected centrally available for study, Elston L. Belknap, M,D Milwaukee, Wise Harry Foreman, M.D, Los Alamos, N.M, Harriet L. Hardy, M.D, Boston, Mass. July, 19$2 Thomas L. Shipman, M.D, Los Alamos, N,M, 2 d issue (1 0 0 ) 9/19 / 5 2 -1 PROTOCOL FOR THE USE OF Ca EDTA IN CASES OF LEAD INTOXICATION AIMS: 1, To test the efficacy of Ca EDTA in accelerating the excretion lead in humans, 2. To determine toxic effects, if any, 3. To obtain data for establishing an optimum .dosage, i;. To determine the best mode of administration of the drug. NECESSARY CLINICAL DATA:1* Name, sex and age, Home Address, Physician in charge, Hospital, Occupational History in the case of an adult, Exposure History in the case of a child, Medical History and Examination 1. Character of onset; presenting signs and complaints, 2. Clinical course, including response to previous therapy, 3. Pretreatment physical examination, with particular attention to: a. Lead line of the gums, b. Involvement of the peripheral nerves by weakness or palsy of extensor muscles, c. Visible jaundice, d. Involvement of central nervous system, i.e. encephalopathy, U. Pertinent laboratory findings: anemia, stippling, reticulocytes; Medical Examination During Treatment Evidence of side or toxic actions in: 1, Cardiovascular system, 2* Gastrointestinal tract, 3 Genitourinary tract, h. Central nervous system, 5. Blood, Appraisal of effects, both objective and subjective] liedical Examination After Treatment Careful obsex'vation for possible reactions for at least a month and at intervals thereafter, depending on the circumstances, NECESSARY IABO.blTQRY DATAl 1, If feasible, starting one week before the beginning of treat ment, collect daily urine specimens and/or blood for lead assay. Continue daily assays for 2-3 days following cessation of treatment. When possible, coproporphyrin studies should be done on the urine. 2, Hematological tests to be done include Hgb, WBC and differential, hematocrit, bleeding and clotting time and bone marrow biopsy (or direct smears if biopsy is deemed impractical) - one set of values pretreatment, 3, Routine urine analysis and Addis count, U. Further studios should include serum calcium and phosphorus if pos sible, total protein A/G ratio, U P N, prothrombin time, urine urobilinogen. For close follow-up of the patient it is urged that certain laboratory tests should be run daily during treatment. These tests are listed below. Other tests should be done as frequently as practical or as circumstances indicate. Hgb, VJBC and differential, Serum calcium ana phosphorus, Prothrombin time, - 3- 03560 Urine urobilinogen, Blood lead and/or urinary lead, Urinan/- coproporphyrin, if quantitative test is available. This follow--up should continue for 3-7 days after the last admini stration of the drug and then at longer intervals as seems wise to the investigator. SUGGESTED DOSAGE; 1. Route: intravenous drip only, not over 0.5 gm per 30 lbs. per hour. 2. Total dose limited to: 1 gm per 30 lbs. body weight per 2b hours. 3. Maximum total dose per week (7 days) of 5.0 gm per 30 lbs. body v/eight in divided doses. b. Limit individual courses of treatment to 10 days, with one week rest period between; 7 .5 gm maximum per 30 lbs. over 1 0 days. TOE HUMAN USE OF ETOYLENEDIAMINETETRACETIC ACID (EDTA) A Compilation of Cases Compound No. Used Dosage Reason for Use 1. 3 oases, Ca EDTA .5 ga in divided Rx of acute Pb children doses to total poisoning of 8 gm 2. 1 child 3. 3 oases Ca EDTA 1 gm dose daily Chronic Fb for 5 days poisoning Ca EDTA 2 gm doses dally Rx of subacute up to a total of Pb poisoning 30 ga in 3 weeks t. 1 case ' Ca EDTA Range from 150 mg Rx of lead age 3 to 750 mg I.V. oneephalopathy daily up to a total of 65 gm 5. 1 case Ca EDTA Range from 100 Rx of beryl age 37 mgm to 10 gm I.V. up to a liosis total amount of 9U.9 6. 60 cases EDTA 1.5 gm combined Anticoagulant with one unit blood 7. 11 cases EDTA 2 to 5 gm daily Controlled I.V. up to 12 gm bone lysis* in 5 days 3. 1 case 9. 5 cases LO. 20*30 oases LU 11 cases 12. 12 cases EDTA EDTA EDTA EDTA Mg EDTA Doses up to a single dose 20 ga I.V. in 20 min .01 M solution as eye wash 5$ solution in water as an ir rigating median Percutaneous ad ministration of ointment con taining 5$ EDTA 120 mg I.V. fol lowed by 180 mg I.V. To lower serum calcium in patient with Ca of breast; with osteolytic lesions Dissolution of calcified pla ques in cornea Rx of ureteral lithlasis Research Rx of hyperten sion 13. 2 tei*- fn-irml cancer cases Ni EDI! 1 gm I.V. Research Therapeutic or Physiological Effect Alleviation of lethargy in 2-3 hrs. Marked in crease in alertness Subjective improvement Decrease in Pb line Increase in red count from 3.9 to 5.2 m. in one month Alleviation of lethargy and twitchlngs. Increase in blood Pb levels Toxio Effects Comments No change in hematological findings. No change in blood chemistry No toxic mani festations Reported bone marrow depres sion Later refuted Rise in NPN up to upper limits of normal None observable; no change in serum Ca, Na and K values Questionable Addis count changes Received ACTO con currently Ref. 1 2 ~ T~ l U None Elevated urinary calcium output. Serum calcium levels maintained. Bone was apparently decalci fied Lowering of serum cal cium from 25 mg/100 cc to 8.8 mg/100 cc in 1 hr Apprehension, headaches, restlessness Blood ele ments well preserved Use of cal cium che late pre vents this 6 7 Favorable results No evidence of toxicity Dissolution of stones Bladder ir ritation Lowering of serum Ca down to 8 mg/100 cc Lowering of systolic pres Depression of Ca sure as much as 80 on Hg and P serum lev for 3--U days. Lowering of els. Ca down to diastolic pressure as much 8 mg/100 cc and as UO mm P to 2 mg/lOOcc None observable None observable 88$ ex- orated in 2 hrs. 100$ in 36 hrs. 8 9, 10, 11 12 13 iJ* References 1. Beasman, S. P., Reid, H. and Rubin, V. Med. innel. District of Columbia, June 1952. 2. Sidburg, S. B., Grady Hospital, Atlanta. Personal communication to U. Rubin. 3. Belknap, E. L. Industrial Medicine and Surgery, 21 305 (1952). It. Personal comunicatioa from H. S. Van Ordstrandj'TTleveland Clinic. Georgetown University Hospital, Washington, D. C. 5. Proescher, F. Proc. Soc. Exp. Biol, and Med., 76 619 (1951). 6. Laalo, D. and Schilling, A., Uonteflore Hospital, N. Y. Communication to M. Rubin. 7. Pellhorn and Schaglen-Edsards. Personal comnunlcation to M, Rubin. 6. Grant, W. M., Harvard University. Personal communication to M. Rubin. 9. Gehres, R. F. and Raymond, S. Journal of Urology, 65 h lh (1951). 10. Abeshouse, B. and Weinberg, T. Journal of Urology,~55 JL6 (1951). 11. Klaeln, B. and Katelson, S. Science, U.2 367 (1950). 12. PopoYicl, A., Qeschickter, C. F. and ftubln, M. Experimental Control of Serum Calcium Levels in Vivo* Proc. Soc. 13. EPxtpop.ovBlicoil,.A&.,MeQde.s,chiIhckt1*e1r5,(C1.950F)..and Rubin, M. *lhe Use of Magnesium in Hypertension* In press. lit. Oesohiclcter, C. F, "Effect of Chelating Compounds on Bodily Distribution of Radio Calcium* Presented at meeting of Bio-Medical Progrsst Directors, Fsb. 20, 1951. DISCUSSION The use of EDTA in humans is still so recent that very few reports have reached the stage of publication. Most of the information contained in this table was obtained by personal communication with the people presently engaged in the work. Because of the current nature of the work, the compilation neces sarily is not complete. It covers, however, most of the cases up to July, 1952, It is surprising that, in view of the recent application of this agent to bio logical problems, there are already over a hundred applications in humans in which the drug or its chelates were administered. There have been eight cases of Fb poisoning treated with Ca EDTA; 5 in children and 3 in adults. In the U acute cases in children there was marked alleviation of symptoms within several hours of treatment. In every case where urinary Pb assays were determined, there was considerable enhancement of Pb excretion following treatment, up as high as a factor of 20 in one case. There was no evidence of toxicity from the use of the drug, nor were there symptoms associated v/ith the mobilization of the Fb. The highest single dose of Ca EDTA that was administered was 10 gm, given to a patient with berylliosis. This patient received a total of 98 grams over a period of 22 days. In a very large series the uncomplexed acid v/as used as an anticoagulant for transfusions into patients. Even in the individuals receiving multiple transfusions there was no evidence of ill effect. In other cases the EDTA was given experimentally to study Ca metabolism. In one striking instance, a terminal carcinoma case with osteolytic lesions, where the serum Ca levels were as high as 25 mg/100 cc, a single dose of 20 grams EDTA was administered intravenously in 20 minutes. The serum Ca level v/as brought down to 8 .8 mg/100 cc in one hour. In other ex perimental studies the Ni and Mg chelates were administered. The use of the Mg chelate resulted in appreciable depression of the serum Ca and P levels. This is to be expected in view .of the fact that Ca will displace Mg from com bination with EDTA and vn.ll be removed from the body as the chelate of the EDTA. Other human applications included such uses as ureteral irrigation to dissolve calculi and eye washes to remove calcific deposits. Topical applications in the form of v/ater-soluble ointments indicate that EDTA is readily carried through the skin. The low toxicity of Ca EDTA is explained by the findings in studies using the Cfu labeled material. The material is excreted unchanged. All of the drug can be accounted for in the excreta. Sixty to 90 per cent of the administered drug is present in the urine after 6 hoursj 95-99 per cent in 25 hours. The remainder is in the feces. Distribution studies reveal no unusual localization of the drug in any organ during the time the material is in the body. 03563