Results of DMSA Treatment Study

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Results of DMSA Treatment Study

• James Adams, Liz Geis, Matthew Baral, Jessica
  Mitchell, Julie Ingram, Andrea Hensley, Sanford
  Newmark, Eva Gehn, Bob Rubin, Warren Tripp, Ken
  Mitchell, Jeff Bradstreet, Jane El-Dahr
• Southwest College of Naturopathic Medicine
• Funded by Wallace Foundation and
• Autism Research Institute

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Current study

• Goal Determine if DMSA/glutathione therapy
  helps children with autism.
• Phase 1 9 doses of DMSA over 3 days, 10
  mg/kg-dose collect urine at baseline, after 1st
  dose, and after 9th dose daily doses of
  glutathione
• - if high toxic metal excretion, continue to
  phase 2
• Phase 2 3 month, double-blind, 1
  round-controlled treatment study
• 3 days on DMSA, 11 days off repeat 6x
• 82 children enrolled
• 65 completed phase 1
• 41 completed phase 2

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Phase 1

• Started with 82 participants
• 1 did not qualify due to elevated liver enzymes
• 4 stopped after physical exam
• 11 stopped after initial blood draw (2 could not
  collect baseline urine)
• 1 collected urine after DMSA but did not send to
  lab (busy family)
• 65 collected urine after DMSA and sent to lab for
  testing

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Toxic Metal Excretion after DMSA 1st 9th
dose changes in median values (N63)
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Loss of essential minerals

• Potassium
• 1st dose lost 27 of RDA
• 9th dose lost 12 of RDA
• So 1st day probably lost about 75 of RDA, 2nd
  day about 55 of RDA, and 3rd day about 40 of
  RDA plt.0000000001
• Equivalent to loss of about 7 bananas worth of
  potassium over 3 days
• However, blood levels normal when tested 3-4
  weeks later, so no long-term effect
• Chromium 1st dose lose 45 of RDA 9th dose
  lose 15 of RDA p0.0005 so, several days of
  DMSA results in several days loss of chromium

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Loss of essential minerals (cont.)

• Molybdenum decreased excretion by 6 on 1st
  day, 30 on 9th dose. Probably not a concern.
• Sodium 1st dose increased excretion of 30,
  normal by 9th dose not a concern
• Copper and Zinc Increased excretion, but less
  than 1 of RDA
• Vanadium small loss (about 1/3 of daily intake)
• Little change calcium, phosphorus, magnesium,
  sulfur, selenium
• Conclusion DMSA causes some loss of potassium
  and chromium, small loss of vanadium excretion
  of other minerals is unimportant
• Recommendation when using DMSA, eat extra
  fruits/vegetables for potassium (cannot
  supplement it), and supplement chromium and
  possibly vanadium.

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Initial Glut 31-1033 - many lower/higher than
adult RR of 427-714 Final Glutathione 355-695
- almost all within reference range For low RBC
glutathione, DMSA greatly increased values to
normal For high RBC glutathione, DMSA reduced
values towards normal
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Why are some RBC Glutathione unusually low and
high?

• Initial glutathione correlates with Pb-9 (.25),
  Sb-b (0.26), Cd-9 (0.30), Al-9 (0.29), and
  inversely correlates with Hg-9 (-.27).
• Hypothesis body responds to Pb, Sb, Cd, Al by
  making more glutathione. But, mercury blocks
  production of glutathione, and decreases it.

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Why does 1 round of DMSA normalize glutathione?

• Change in glutathione correlates with Hg-9
  (0.31), and inversely correlates with W-9
  (-0.45) and Cd-9 (-0.47).
• So, removing some mercury increases low
  glutathione, and removing tungsten and cadmium
  reduces high glutathione.

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Changes in Blood Chemistry after 1 round of DMSA
(measured 3-6 weeks later, n41)

• Major Tests no major problems, possible
  improvement of kidney function
• White Blood Cell -3
• Platelet Count -6, p0.02 (12/42 high, 1 low
  then 6/42 high, 0 low)
• Lymphocytes -4
• Potassium 1
• ALT (liver enzyme) 4
• AST (liver enzyme) 0
• BUN/creatinine -6, n.s. (17/42 high, 0 low,
  then 14/42 high, 1/42 low)
• Creatinine -2 (0 high, 8/42 low, then 0 high,
  9/42 low)
• Other changes (none were statistically
  significant)
• Basophils 24
• Bilirubin -15, n.s.
• Suggests no major safety concerns for 1 round
• Platelet levels improve (less inflammation)
• BUN/creatinine often high, since creatinine low,
  BUN high

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Transition to Phase 2

• 8 children not allowed to continue due to low
  excretion of toxic metals
• 1 child not allowed to continue due to extremely
  high lead
• 1 family left on extended travel
• 1 family wanted to try other treatments
• 1 child discontinued due to extended use of
  antibiotics due to urinary tract infections
• 1 family too busy/overwhelmed
• 1 child had extreme anxiety over blood draws
• 1 wanted to start private treatment (avoid risk
  of placebo)
• 1 had mild adverse reactions (lethargy, increased
  appetite)
• 49 continued to Phase 2

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Phase 2 Randomized, double-blind,
placebo-controlled

• 2 dropped due to family reasons (parents busy,
  parent died)
• 2 dropped due to lack of improvement
• 4 dropped due to behavior problems
• Mild slept very little, but not tired (on DMSA)
• Moderate behavior worsened, more stimming (on
  placebo)
• Moderate behavior worsening, regressing (on
  placebo)
• ???? parents reported gain and lose skills,
  similar pattern for 2 years prior to study, but
  ADOS scores improved (on DMSA)
• 41 finished full study, including 4 in treatment
  group who finished early due to low excretion
  after 3rd round

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Long-term Effect of DMSA on Urinary Excretion of
Toxic Metals Changes in Median
ValuesTreatment Group Only (n26)
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Summary of long-term metal excretion

• For 5 children, DMSA treatment resulted in
  substantial decrease in excretion of lead, so
  they were only treated for 3-4 rounds
• For most of the children receiving DMSA (19),
  lead excretion continued at a high level.
• Moderate excretion of mercury, tin, thallium.
• Al excretion initially decreased, then increased.

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Changes in Blood Chemistry after 7 rounds of DMSA
n21

• No major problems platelets improved kidney
  function remains abnormal
• Platelets -18, p0.05
• (initially 10 high, 1 low to 4 high, 0 low
  improved!)
• White Blood Cell -7 n.s. (initially 1 high, 0
  low then 1 high, 1 low)
• Lymphocytes 0
• Potassium 0
• ALT (liver enzyme) 3 - initially 1 high, then
  all ok
• AST (liver enzyme) -6 - all normal
• BUN/creatinine (kidney) 8 - initially 10 high,
  then 9 high, 1 low
• Statistically Significant changes
• Triglycerides 47, p0.06 (trend) - initially
  zero high, then 2 high
• Other changes (not significant)
• Eosinophils -19, p0.08 3 high, then 2 high
• Basophils 50, n.s. - all normal
• Alkaline Phosphatase 12, n.s. all normal,
  then 5 high (growth spurt?)

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Changes in blood chemistry after 1 round DMSA, 7
rounds placebo

• Platelets -13, p0.01 initially 1 high, then
  all normal measured 3-4 months after treatment,
  so effects are long-lasting
• Similar to 7 dose case (-18)
• Nothing else significant (no long-term effects
  safe)

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Regression analysis of Platelets

• Change in platelet level could be partially
  explained (adjusted R20.41, p0.02) with major
  factors being excretion of Thallium (p0.002),
  Arsenic (p0.01), Cadmium (p0.03), and change in
  glutathione (p0.04)

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Evaluations of Autism Symptoms

• Parents
• Severity of Autism Scale
• ATEC parents
• PDD-BI
• Global Impressions
• Research-certified professionals did ADOS

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Severity of Autism Scale

• 0-10 point scale
• 7 round group -18 (improvement)
• 1-round group -18 (improvement)
• Significant improvement in both groups.

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ATEC Results
Scale 7 rounds 1 round
I. Speech/Language Comprehension -21 -13
II.Sociability -27 -25
III. Sensory/ Cognitive Awareness -27 -26
IV. Health/ Physical/ Behavior -28 -15
ATEC Total -26 -19
Both groups significantly improved 7 round group
improved more in Language, Physical Health, and
Total ATEC, but not statistically significant
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Pervasive Developmental Disorders Behavior
Inventory (PDD-BI)
Significant improvement in both groups
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Overall Impressions - Results

• Based on parent evaluations on final day of study
• 7 point scale
• 3much better
• 2better
• 1slightly better
• 0same
• -1slightly worse
• -2worse
• -3much worse

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Parent Global Impressions
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Parent Impressions- Overall
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ADOS exam

• Autism Diagnostic Observation Schedule
• Based on 1-hour standardized interaction with
  child by ADOS-certified professional
• One of the gold standards for evaluating
  severity of autism

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ADOS results
7 rounds 1 round Communication -9 -11 Social
Interaction -10 -2 Play/Creativity -5 0 SBR
I (stereotyped behavior and restricted
interests) -9 -2
ADOS less sensitive than other instruments
(developed to diagnose autism, not monitor
changes). Overall, 7-round group improved
slightly more, but not significant difference
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Summary of Autism Evaluations

• Significant improvements on all scales for both
  groups
• 7 dose group had slightly better improvements on
  ATEC and ADOS, but not statistically significant
• Similar improvements in PDD-BI, SAS, Global
  Impressions
• Since most kids still excreting high amounts of
  lead after 7 rounds, suggests longer treatment
  needed to reduce lead excretion.
• Question would longer treatments result in more
  behavioral improvements?

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Why little difference between 7 rounds and 1
round?

• Hypothesis 1 DMSA ineffective on autism
  symptoms (placebo effect).
• Hypothesis 2 1st round of DMSA normalized
  glutathione and improved platelet levels, so that
  further treatment had little additional effect.
• Correlations of behavioral improvement with
  biochemical changes suggest hypothesis 2 is
  correct.

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Overall change in autism severity, including both
7-round and 1-round groups
Improved No Change Worsened
ATEC 96 2 2
SAS 61 33 6
ADOS (Comm. Social) 68 15 17
PDD-BI (modified Autism Composite) 75 2 22
Parent Global Impression 86 8 6
Average of all 5 assessments 77 12 11

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Regression Analysis Severity of Autism

• Compare severity of autism with glutathione and
  metal tests
• adjusted R2 Most significant metals
• ATEC 0.22 p0.003 Pb-9, Sb-b
• SAS 0.36 p0.002 Pb-b
• PDD-BI 0.25 p 0.004 Sb-9, W-b, Sn-9
  
• ADOS 0.49 p0.0003 Hg-b, Al-b, Hg-9
• All four scales of autism severity can be
  partially explained in terms of heavy metal
  excretion, with a very high statistical
  significance.
• Suggests 22-49 of autism severity appears to be
  due to toxic metals, especially lead, antimony,
  and mercury.

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Regression Analysis Improvement

• Compare improvements in severity of autism with
  glutathione and metal tests
• adjusted R2 Most significant metals
• ATEC 0.44 p0.006 Hg-9, As-9
• SAS 0.57 p0.002 Tl-9, Pb-9, glut change
• PDD-BI 0.75 p0.0006 Tl-9, As-9, glut change,
  Pb-9, Sb-9
• ADOS 0.28 p0.02 As-9, Al-9
• Changes in all four scales can be partially
  explained (28-75) in terms of urinary excretion
  of metals
• Arsenic, thallium, lead, and change in
  glutathione are most important
• When glutathione increases, symptoms generally
  decrease.
• When metal excretion increases, symptoms
  generally decrease

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Effect of Age on Improvement

• Slight negative correlation suggests that older
  children possibly tended to improve slightly more
  than younger children (not significant)
• Test Correlation with age
• ATEC -.20
• SAS -.19
• PDD-BI -.12
• ADOS -.06

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Conclusions - benefits

• DMSA greatly increases excretion of lead, and
  some increase in excretion of tin, mercury,
  thallium.
• 1 round of DMSA dramatically normalized
  glutathione levels for at least 1-2 months, and
  helped normalize platelet levels (marker of
  inflammation) for at least 4 months

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Conclusions - safety

• DMSA increases excretion of potassium and
  chromium suggests need for more vegetables/fruit
  and modest chromium supplementation during
  chelation
• DMSA had little effect on other essential
  minerals
• DMSA had no adverse effect on liver enzymes,
  kidney function, or complete blood count (CBC)
• DMSA possibly raised triglycerides concern to
  watch for
• Check cysteine levels, since 90 of DMSA is
  excreted bound to 1-2 cysteine.

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Conclusions Effect on Symptoms

• Both groups had significant improvements on
  autism scores
• 7-round group had slightly more improvements on
  ATEC and ADOS, but not significant
• More improvement in those with low glutathione
  and high initial metal excretion strong
  correlations and regression analysis strongly
  suggest that improvement is real (not just
  placebo effect)

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Bottom Line

• Toxic metals (especially lead, antimony, and
  mercury) account for 22-49 of autism severity.
• DMSA is a safe way to remove toxic metals,
  normalize glutathione, normalize
  platelets/inflammation
• Correlation of improvement in autistic symptoms
  with glutathione and metal excretion suggests
  DMSA did result in reduction of some symptoms of
  autism.
• Longer treatment needed by most children to
  decrease lead levels unknown if longer
  treatment might provide additional behavior
  benefit.
• Double-blind, placebo-controlled study of DMSA
  needed
• Other chelators may be needed for mercury and
  other metals (arsenic, antimony).
• More research should be done!

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Questions

• Will longer treatment with DMSA result in more
  benefit?
• Probably, but need to study
• How to test for and remove antimony?
• DMPS, somewhat Ca-EDTA
• How to test for and remove mercury?
• DMPS challenge, urinary porphyrins, other

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Acknowledgements

• Many children and parents who participated in the
  study
• ARI and Wallace Foundation for funding
• Doctors Data for urine testing
• Immunosciences for RBC glutathione and immune
  testing