Detoxamin

ORIGINAL COMMUNICATIONS

A PILOT DOUBLE BLIND STUDY OF
SODIUM MAGNESIUM EDTA IN
PERIPHERAL VASCULAR DISEASE

Efrain Olszewer, MD, Fuad Calil Sabbag. MD, and James P. Carter, MD, DrPH New Orleans, Louisiana Ten male patients with peripheral vascular disease, Type 2 (LaFontaine), were randomly assigned in a double-blind study to receive either Na2 ethylene diamine tetra acetic acid (EDTA) plus MgSO₄, B complex, and vitamin C, or a placebo of MgSO₄, B complex, and vitamin C in Ringer's lactate solution. A total of 20 Intravenous infusions were planned for administration to each patient. Clinical and laboratory (noninvasive) tests showed dramatic improvements after 10 infusions in some patients, and thus was broken the code indicating who was receiving EDTA and who was receiving placebo. The group that improved had been receiving EDTA; there was no change in the placebo group. The trial was than completed in a single-blind fashion. Patients originally assigned to receive placebo then received 10 EDTA Infusions, while the group originally assigned to EDTA received 20 EDTA Infusions.

The group that had formerly received placebo showed improvements comparable to those seen in the first EDTA group after 10 treatments.

To our knowledge, no one has yet published a double-blind study evaluating the effectiveness or NaMg EDTA in the treatment of peripheral vascular disease.¹ Some case reports and retrospective studies, including our recent review of 2870 cases of chronic degenerative disease treated with EDTA, have been published.^2,3 We, therefore, conducted a pilot double-blind clinical trial of EDTA in peripheral vascular disease

METHODOLOGY

Ten patients, all male, with a mean age of 47 years (range 41 to 53), and all with peripheral vascular disease from diabetes or arteriosclerosis, aggravated by smoking, were enrolled in the study. They were all stage 2 of the LaFontaine Classification, which means that they had intermittent claudication, but no pain at rest or in the night, and no gangrene. They included eight former heavy cigarette smokers, all of whom had quit at least 6 months before the study began.

Clinical evaluation included the following:
Peripheral vascular signs (skin disturbances, temperature, hair changes, etc), kidney function, blood pressure (BP). and BP index comparing the ankle systolic BP to the arm systolic BP, with a mean index of no higher than 0.75 or no lower than 0.40. The Walking Test included patients with claudication between 100 and 300 meters. The Master "Two Step" Exercise Test included patients with claudication with less than 40 steps, and the Bicycle Stress Test included patients with claudication before 3 minutes at 50 kilometers per hour.

The ten patients were randomly and equally divided into two groups, receiving ampules of 10 ml of EDTA or distilled water (numbered from I to 10), with the identification of the contents of each vial in a sealed envelope by the manufacturer (Mezquita Laboratories. Sao Paulo). Both groups received the usually administered nutritional additives to the intravenous solution, vitamin C, (2 grams), B complex (2 mL), vitamin B6 (300 mg), heparin 500 lU, magnesium sulfate (1 g).6 Na2, EDTA was used in a dose of 1.5 g for each infusion. The EDTA and distilled water were supplied in white bottles of 10 mL, numbered from I to 10 for identification purposes (five water and five EDTA).

RESULTS

Tables 1 and 2 show the results obtained in 10 patients after 10 chelation treatments and 10 placebo treatments. There was a substantial improvement in before and after measurements for the Walking Test and for the Master Exercise Test. The minutes and seconds the patient could pedal on the bicycle stress test are also given in Table 1, before and after 10 treatments. Values for both groups, before and after 20 treatments, are also included in Tables I and 2.

TABLE 1 IMPROVEMENTS IN PERFORMANCE BEFORE AND AFTER THERAPY WITH EDTA AND PLACEBO

Before EDTA				After 10 Sessions			Final
Patient	Walking (meters)	Masters (steps)	Bicycle (25 km/hr)	Walking (meters)	Masters (steps)	Bicycle (25 km/hr)	Walking (max distance)	Masters (max steps)	Bicycle (max time)
E1	180	32	3'30	450	58	6'5"	760	70	9'
E2	200	36	4'50"	220	35	4'35"	480	52	6'
E3	150	32	3'10"	400	58	6'	620	68	8'15"
E4	120	24	3'15"	350	50	5'50"	480	64	7'55"
P5	150	30	3'30"	140	31	3'20"	350	52	5'50"
P6	200	35	4'35"	250	38	4'40"	550	56	7'55"
E7	250	40	5'10"	600	70	6'	770	70	9'
P8	180	30	3'25"	190	30	3'20"	350	48	6'15"
P9	230	38	4'55"	250	40	5'05"	480	63	7'30"
E10	100	18	3'10"	320	46	4'55"	380	50	6'45"

E = EDTA
P = PLACEBO

TABLE 2 OVERALL IMPROVEMENT RATIOS COMPARED WITH BASELINE VALUES

Group assigned to EDTA				Group assigned to Placebo
Method	Rest to 10 treatments	10 to 20 treatments	Rest to 20 Treatments	Rest to 10 Sessions	10 Placebo to 10 EDTA treatments	Rest to 10 EDTA treatments After 10 Placebo treatments
Walking	2.65	1.42	3.76	1.1	2.08	2.30
Masters	1.86	1.07	2.00	1.02	1.94	2.00
Bicycle	2.10	1.44	3.04	1.01	1.60	1.60
Mean	2.20	1.31	2.93	1.04	1.87	1.96

TABLE 3 BLOOD PRESSURE INDEX, AT REST AND AFTER EXERCISE, BEFORE AND AFTER THERAPY WITH EDTA AND PLACEBO

Group Assigned to EDTA				Group Assigned to Placebo
	Baseline	10 EDTA	20 EDTA	Baseline	10 Placebo	10 placebo/10 EDTA
Rest	0.66	0.89	0.95	0.62	0.63	0.86
Exercise	0.54	0.78	0.88	0.56	0.54	0.75

BP INDEX = Systolic ankle BP/Systolic arm BP

After 10 treatments, it was apparent that some patients were improving substantially but others were not. We therefore decided to break the code. This showed that only patients assigned to receive EDTA were improving. We therefore decided on a single blind basis, to give EDTA to all patients for the remaining 10 sessions. The results obtained in the placebo group, after 10 treatments with EDTA (20 treatment sessions total), were similar to the group originally assigned to EDTA, after the first 10 treatment sessions. In the original EDTA group, we also noted an additional improvement from the 10th to the 20th chelation treatment, but not as much as the improvement from baseline to the end of the 10th. (Table 4.)

TABLE 4. DIFFERENCES BETWEEN BASELINE AND 10 AND BASELINE AND 20 SESSIONS, COMPARING ACTIVE AND PLACEBO GROUPS AND TESTING FOR TREATMENT EFFECT OVER TIME

Outcome Variable	Treatment Effect	Time Effect	Treatment by Time Effect
Walking	P = .06	p = .000	P .0003
Masters	P = .07	p = .ooo	P - .000
Bicycle	P = .1018	p = .000	P = .00001
BP Index at Rest	P = .005	p = .000	P = .0006
BP Index on Exercise	P = .001	p - .000	p - .0042

The EDTA group after 10 infusions doubled the distance walked before therapy (x2.2), compared with essentially no change in the placebo group (x I .04). After the 20th infusion, the EDTA group walked nearly three times ( X 2.93) the distance, and in the placebo group, after we introduced EDTA they improved approximately 100% (x 1.96). The improvement in the original EDTA group from the 10th to the 20th session was 31% (x 1.31).

We also studied BP index, comparing the ankle BP to the arm BP, as shown in Table 3- The differences in improvements in the patients treated with EDTA, compared with the patients treated with the placebo can also be readily discerned.

DATA ANALYSIS

The best method to analyze these data was the repeated measures method, as we measured the parameters more than once and we repeated those measures. As our model contains dimensions of both treatment effect and time, the interaction between treatment and time in many cases is strong enough to absorb the effect of treatment alone. This interaction is significant in this study. This means that the effect of treatment is increased with time. Hence, there is an even greater difference between the groups than appears at first glance. The data analyses are statistically significant. There is only borderline significance between the baseline measures and after 10 treatments with respect to the Walking and the Master Step Tests (P=.06 for the Walking and P = .07 for the Master Step). At the same time, however, there were time effects and significant differences for the interaction between group and time (P=.025). The results showed no group differences between baseline treatments and 10 treatments. This is probably related to the fact that the placebo group only started to receive EDTA after 10 sessions.

To ensure that there is a group effect, we analyzed these data between 10 treatments and 20 treatments. The results showed that there were group effects and time effect, besides group by time effects. (Table 5)

TABLE 5 DIFFERENCES BETWEEN 10 AND 20 SESSIONS, COMPARING ACTIVE AND CONTINUOUS VERSUS CROSSOVER (FORMERLY PLACEBO) TREATED GROUPS AND TESTING FOR TREATMENT EFFECT OVER TIME

Outcome Variable	Treatment Effect	Time Effect	Treatment by Time Effect
Walking	P = .0255	p = .060	p - 3.06
Masters	P = .0069	P = .0056	P = .0056
Bicycle	p = .013	P = .000	P- .662
BP Index at Rest	P = .0005	P = .0004	p = .0097
BP Index on Exercise	P = .0002	p = .0002	p = .0652

These results suggest that EDTA had a significant impact in causing the improvements seen in the patients' clinical status at the 0.05 level of significance.

DISCUSSION

In our retrospective analysis of 2870 cases,⁵ we showed marked symptomatic improvements in patients with chronic degenerative diseases when they were treated with EDTA chelation therapy. These patients were used as their own controls. The findings were very similar to the original descriptive data of Clarke^6-8

Other studies have been done to determine the efficacy of NaMg EDTA chelation therapy^6-9 Its safety, when administered according to the American College of Advancement in Medicine protocol,¹⁰ is no longer a major concern, in view of the fact that more than 500 000 patients have been treated in the US alone, without a single reported incident of renal failure or death since 1960. This was not always the case, because in the l95Os, patients were not routinely screened with sequential multiple analyzer computerized (SMAC) 20, creatinine clearance, or electrocardiogram. Further, most case reports of patients who developed renal failure were given more than 3.0 gms of EDTA per infusion or had lead poisoning, with the formation of lead complexes in the kidneys. We believe that the present study, however, is one of the first to use a randomized, placebo-controlled double-blind design.

Current knowledge allows us to speculate that chelation therapy with EDTA may work by the following mechanisms. EDTA acts first in the vascular compartment by binding ionic calcium and other divalent cations and trace elements such as zinc and transporting them in bound form out of the body in the urine; High levels of zinc in relation to copper can also have an adverse effect on cholesterol and lipoprotein metabolism.¹¹ By lowering the serum calcium, it evokes a parathyroid response to secrete parathormone which pulls calcium out of the bones and causes the kidney to excrete phosphorus in order to stabilize a normal calcium/phosphorus ratio.

Also, in the vascular compartment EDTA decreases platelet aggregation.¹² Some of the effects of EDTA when incubated with platelets are reversible after subsequent calcium addition, while others are not. Therefore, EDTA must have at least two different modes of action on the platelet, one being simple calcium deprivation of the extracellular compartment. But there must be one or other modes of action: one may be irreversible alteration of platelet membrane calcium-binding capacity. EDTA may effect a final common pathway of aggregation, possibly the rise in intracellular calcium.¹³

EDTA also acts at the level of the cell membrane by removing Fe and Cu, the principal catalysts of lipid peroxidation of the long-chain unsaturated fatty acids in the membrane, with the generation of free radicals and disruption of membrane architecture, including calcium transport channels.^4,5 In the presence of ischemia, this membrane damage results in an influx of calcium into the cell and mitochondrion, resulting in intracellular calcium accumulation.^16-18

When some of this intracellular calcium is chelated and removed by EDTA, there is:

1. An increase in vascular diameter of the arteries of at least l0%,^19-22 enough to double the blood flow, possibly due to decreased muscle contraction.
2. A decrease in vascular tone and conriactility.^9-22
3. A decrease in peripheral resistance by removing intracellular calcium from ischemic tissues, allowing collaterals to grow around occluded vessels.²³

Chelation with ruthenium red has been shown to reverse calcium influx in the heart and bring about improvements in mitochondrial energy production and ventricular performance (especially in diastole) in the pig model.^{18, 24-25} (Personal communication regarding use of EGTA for the same purpose. American College of Advancement in Medicine. May 9 to 15, 19S8, New Orleans.)

Acknowledgements

This paper is dedicated to the memory of Dr Michael Taiar wno made significant contributions to this research. His death was a great loss to his patients and to his colleagues. Thanks also go to Mezquita Lab. Sao Paulo which prepared the solutions, to the staff of the International Institute of Preventive Medicine, Sao Paulo, for their assistance in patient care and evaluation, to Ahmed Bahnassy for help with the statistical analyses, and to Dr Ross Gordon of the American Institute of Medical Proventics for his support and encouragement. From CEMIO. Sao Paulo, Brazil, an affiliate of the International Institute of Preventive Medicine, Rua Tamadi 320 Perdizes 05002 Sau Paulo, Brazil, Requests for reprints should be addresses to Dr. James P. Carter, Tulane University School of Public Health and Tropical Medicine, 1501 Canal Street, Suite 809, New Orleans, LA

Literature Cited

1. Perry. JR. Chelation therapy in circulatory and sclerosing diseases Fed Proc. 1961;20:254-57.
2. Casdorph R Farr C. EDTA chelation therapy Ill. treatment of peripheral arterial occlusion, an alternative to amputation. J Holist Med. 1983;5:3-15.
3. Casdorph R. EDTA chelation thorapy I, efficacy in arterioscIerotic heart disease. J Holist Med. 1981;3:53-59.
4. Casdoiph R. EDTA chelation therapy II. Efficacy an brain disorders. J Holist Med'. 1981 3:1O1-1 17.
5. Olszewer E. Carter J. Disodium magnesium EDTA chelation therapy in chronic degenerative disease: A retrospective study. Med Hypoth. 1988:27:41-49.
6. Clarke NE, Clark C, Mosher A. Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. Am J Med Sci, 1956:232:654-666.
7. Clark NE. Treatment of occlusive vascular disease with di-sodium ethylene diamine tetraacetic acid (EDTA). Am J Med Sci. 1960;239:732-744.
8. Mitchell M. The Treatment of Coronary Heart Disease with EDTA, in: Metal Binding in Medicine. In: Marvin J. Seven. ed. Proceedings of a Symposium Held May 6-8, 1956. Philadelphia. PA: J.B. Lippincott; 1960:43-47.
9. Lamar CP. Chelation endartorectomy for occlusive atherosclerosis. J Am Genes, Soc. 1966:14:272294.
10. American College of Advancement In Medicine. Protocol ofi the American College of Advancement In Medicine for the Safe and Effective Administration of EDTA Chelation Therapy, 1989; Laguna Hilts, CA.
11. Klevay LM. Coronary heart disease: The zinc/copper hypothesis. Am J Clin Nutr. 1975:764-774,
12. Van Der Schaar Jr PJ, Van Der Schaar PJ. Some in vivo effects of EDTA on platelets. Presented at meeting of the Amencan Academy of Medical Preventics; May 25. 1988; Washington, DC.
13. Peerscke El, Grant RA, Zucker MB. Decreased association of 45 calcium with platelets unable to aggregate due to thrombasthenia or prolonged calcium deprivation. B, J Heomatol. 1980;46:247-256.
14. Olszewer E. Radicais libres e isquemia por reperfusao. Gac Med Bol. 1988;12:2:74-77
15. Tappel Al. Lipid peroxidation damage to cell components. Fed Proc. 1973;32:1870-74.
16. McCord JM. Oxygen-derived free radicals in post ischemic tissue injury. New Eng J Med. I 985;312.(3):1 59-163.
17. Peng CF Murphy ML Straub KD. Deviant cation-activated ATP hydrolysis by mitochondrial ATP'ase- mechanism for energy depletion in ischemic reperfused myocardium, Cell Calcium. 1982;3(3):227-241.
18. Peng CF. Davis JL. Murphy ML Straub KD. Effects of reperfusion on myocardial wall thickness, oxidative phosphorylation, and Ca2+ metabolism following total and partial myocardial ischemia. Am Heart J. 1986;1 1 2(6):1 238-44.
19. Zechmeister A. Malrriovska V. Hadasova E. of al. Effect of glucagon on lipid and calcium deposition in arterial wall. Folia Morphol. 1979;27:23.26.
20. Zechmeister A. Guida O. Subcellular metabolism of Ca2 + in smooth muscle and myocardium (an ultrahistochemical study). Folia Morphol. 1981;29:333-335.
21. Malinovska V. Zecchmeister A Malinovka L et al. The therapeutic effect of glucagon and chelation Ill on the arterial wall aflter experimental Iipidosis and calcification. Scripta Medica. 1983:56:391-400.
22. Brucknerova 0. Tulacek J. Chelates in treatment of occlusive atherosclerosis. Vinitr Lak. 1972:18:729-735.
23. Bricknerova 0, Malinoyska V. First clinical experience with combined treatment with chelation ill and glucagon in ischaemic disease of the lower extremities. Cas lek Cask. 1980;119:814-81 5,
24. Peng CF. Kane JJ. Straub KD. Murphy ML Improvement of mitochondrial energy production in ischemic myocardium by in vivo infusion of ruthenium red. Cardiovasc Pharmacol. 1980;2(1 ):4554.
25. Murphy ML Pang CF. Kane JJ Jr. Straub KD. Ventricular performance arid biochemical alteration of regional ischemic myocardium after reperfusion in the pig. Am J Cardiol, 1982; 50(4):821 '828.