1. The Use of Actos® (pioglitazone) in the Treatment of Autism Spectrum Disorders Whole Health & Wellness Phillip C. DeMio, MD, Medical Director Angela Shoemaker, Physician-To-Parent Liaison 733 Lakeview Plaza Blvd. 320 Orchardview Ave. Suite G Suite 2 Worthington, OH 43085 Seven Hills, OH 44131 614-436-2036 216-901-0441 © Phillip C. DeMio 04/08

2. Actos in ASD  Actos is a Glitazone  A group of medications marketed/approved for diabetes in U.S. & internationally  Off-label use for Immune System  Variety of glitazones researched as such for many years  Employed clinically as such for 7 years  Initally in MS, then others  4 years now for ASD

3. What are the Actions of Glitazones?  Depends on the organ we’re considering  Eg, pancreas vs. muscle vs. white blood cells  Connects to which disease/symptoms we’re considering  Glitazones have their effects (including “side” effects) no matter what we’re considering!  This is true of all drugs and all supplements and all treatments!  Connects to off-label & novel uses of medications and supplements

4. Consider White Blood Cells as an Organ  T-Lymphocytes  Are white blood cells (WBC’s)  The Generals of the Immune System  Eg. Th-1 and Th-2  Excess Th-2 activity means autoimmunity, allergy, and lowered healthy immunity

5. What Happens in Kids with ASD who have Abnormal Th-1/Th-2 Function?  Immune dysfunction, autoimmunity and, allergy in ASD affects:  Brain/nerves  Gi tract/dysbiosis  Lungs/respiratory/sinus systems  Thyroid (and other hormonal organs)  Frequent severe infections/fever  Other/adult immune problems as mentioned  Allergy (skin, respiratory, food) © Phillip C. DeMio, MD 2005

6. Abnormal Th-1/Th-2 Function, cont’d  This connects to variants of ASD:  OCD  Tics/Tourette Syndrome  Immunity/autoimmunity/allergy (asthma)  RAD  Clinical and laboratory abnormalities  Parents, siblings, and other relatives of persons with ASD (“later onset”)

7. Actos’s Effects on Lymphocytes  Actos shifts Th-2 back to Th-1 activity  Apoptosis  Now the generals can run the troops properly!  Ie, aim at the bad guys, no friendly fire, and no civil war.

8. Goals in the Use of Actos in ASD  Improve the GI tract RE: leaky, & dysbiosis  Reduce/eliminate frequent infections (But Angie & Dr. D.: my kid never gets sick!)  Reverse autoimmunity (brain, gi, thyroid, etc.)  Improve or eliminate allergy (and steroids, and aerosols, and antihistamine drugs…)  Reduce viral load & dormant infectious agents  The ultimate goal is better health and cognition

9. Pragmatics of Actos in ASD  Tablets, patented, lactose, not SCD legal  Transdermal (Lee-Silsby)  Cost; Avandia  Diabetic kids with ASD: switch!  Actos has 15 & 30 mg sizes  Ramp the dose: begin with7.5 mg/day or less, and go up, usually to 30 mg in 7.5mg jumps.  I do not presume “target” doses: one size fits none!

10. Pragmatics of Actos in ASD  Some patients sustain steady improvement with no problems…  But there are potential undesired (“side”) effects with any treatment that is powerful enough to help our kids!  Early mild effects, almost expected include: brief fever, GI “die-off (B & B),” and seeming mild “viral” infections (with or without rashes)

11. Pragmatics of Actos in ASD  More intense undesired effects: prolonged high fever, more marked signs of infection (viral upheaval), regressions, brisk increases in OCD’ish behavior, and diarrhea or abdomenal pain  Hypoglycemic-like effects and low metabolic substrates: skinny kid, poor eater, intercurrent illness (see above), PM dosing, & mitochondrial/acidotic kids  Fluid retention  One child’s opisthotinos: ?pain, lactose, or spasm

12. Pragmatics of Actos in ASD: a Few Comments  Overall safety  Comparing td with oral routes  Follow-up blood tests (organ support)  Time course of expected gainshow long do we “wait?” (cases without intense undesired effects)  Blending with other therapies: HBOT, LDN, antivirals, etc.

13. Pragmatics of Actos in ASD  Let’s revisit the cases that have intense or brisk undesired effects  “Foot in the door”  What does it mean?  Not throwing the baby out with the bathwater  PULSING the Actos!

14. Low Dose Naltrexone in the Treatment of Autism Spectrum Disorders Phillip C. DeMio, MD 320 Orchardview Ave. Suite 2 Seven Hills, OH 44131 216-901-0441 www.drdemio.com © Phillip C. DeMio, MD 2005

15. Low Dose Naltrexone (LDN)   Orginally for heroin addiction/opiate addiction. (Depade®, formerly Trexan®, ReVia®   Concept behind such treatment   Opiate receptors   Drugs   Endorphins/opiate peptides © Phillip C. DeMio, MD 2005

16. Low Dose Naltrexone (LDN) cont.   “side” effects of such treatment   Depressed mood   Respiratory symptoms   “hidden” immune toxicity   Other abnormal immune symptoms: brain; others   “sub clinical” rise in endorphins   …but fully blocked by the high dose of Naltrexone   This led to the syndrome of opiate/endorphin withdrawal -agitation -respiratory (SOB, huffing, stuffy, cough) -diarrhea/cramps -“crawling skin”/gooseflesh © Phillip C. DeMio, MD 2005

17. Opiate Peptides, Naltrexone, and the Immune Connection   T-Lymphocytes   Are white blood cells (WBC’s)   Eg. Th-1 and Th-2   Excess Th-2 activity means autoimmunity, allergy, and lowered healthy immunity   Peptides   Those from gluten, casein, and others (“exorphins”) cause peptide-specific Th-2 stimulation (increased activity)   That makes people sick! (symptoms in: ASD, MS, ALS, IBD, HIV, RA, SLE, asthma, allergy, and cancer to name a few) © Phillip C. DeMio, MD 2005

18. Immune Connection cont.   Endorphins   Compete with exorphins   So endorphins redirect Th-2 WBC’s away from allergy/autoimmunity   Endorphins also stimulate healthy immunity (by heightening Th-1 activity)   Endorphins are abnormally and strikingly low in children and adults who have ASD (and MS, ALS, IBD, HIV, RA, SLE, asthma, allergy, and cancer) (c) Phillip C. DeMio, MD 2005

19. Low-Dose Connection   Recall the rise in endorphins with full dose Naltrexone   “side effects can be good” (a clue, a foot in the door)   But full dose Naltrexone blocks the endorphins © Phillip C. DeMio, MD 2005

20. Low-Dose Connection, cont.   Why the low dose?   Naltrexone at low dose retains it abliity to cause an endorphin rise   If the dose is low enough, the endorphin- blocking effect of Naltrexone is gone in as little as two hours   So most of the day yields higher endorphins   They are not blocked   They are free to “do good” (immune; other) © Phillip C. DeMio, MD 2005

21. Low-Dose Connection, cont.   Great benefit for ASD (and MS, ALS, IBD, HIV, RA, SLE, asthma, allergy, and cancer)   The dose:   Less than one tenth the orginal dose used for addiction.   Currently the target doses are:   3mg/24 hours if less than 45kg   4.5mg/24 hours if over 45kg   We will revisit “the”dose © Phillip C. DeMio, MD 2005

22. LDN in Clinical use for ASD   Immune dysfunction, autoimmunity and, allergy in ASD affects:   Brain/nerves   Gi tract/dysbiosis   Lungs/respiratory/sinus systems   Thyroid (and other hormonal organs)   Frequent severe infections/fever   Other/adult immune problems as mentioned   Allergy (skin, respiratory, food) © Phillip C. DeMio, MD 2005

23. Clinical use, cont.   This connects to variants of ASD:   OCD   Tics/Tourette Syndrome   Immunity/autoimmunity/allergy (asthma)   Clinical and laboratory abnormalities   Parents, siblings, and other relatives of persons with ASD (“later onset”) © Phillip C. DeMio, MD 2005

24. Clinical Use, cont.   Preparations   Topical or oral   Currently, same dose for each   Swallowing, taste, and timing issues   11pm dose   Maybe oral is better if:   Constipated   Crampy   Diarrhea: start with topical   What about gluten and casein?   Make exorphins   LDN may cause withdrawal if not gf/cf   But may actually cause improvement   We will revisit the dose © Phillip C. DeMio, MD 2005

25. Clinical Use, cont.   Sources   Coastal Compounding Pharmacy (topical)   Lee-Silsby Compounding Pharmacy (topical or oral)   Others (experience/communication)   Dr. McCandless after Dr. Bihari: Many responders   More science and numbers than Dr. Kanner! © Phillip C. DeMio, MD

26. What to Expect in Clinical Use   “Effects”   Bowels and brain   Immune system   They overlap!   “Side” effects   Bowels and brain   Immune system   Stimulation   “good”: endorphins/transient   “not good”   Die-off   Excess blockade of endorphins   Constipation/agitation/sensory issues © Phillip C. DeMio, MD 2005

27. Other Clinical Issues   Itching and rash   Unique situations   Opiate drugs   Pain   Anesthesia   Clonidine/guanabenz   Enzymes   Long term   Will effects sustain?   Experience outside of ASD © Phillip C. DeMio, MD 2005

28. Revisiting the Dose   Kids/adults can get the “not good” responses   Some patients may not sustain   Revisiting the dose   Unsustained group   Raise the dose (chasing your tail?)   Pulse dose   Kids on gf/cf diet   Ultra-low-dose Naltrexone   Start low and slow © Phillip C. DeMio, MD 2005

29. LDN Conclusion   Ultimately, as with other treatments   Naltrexone helps many persons   May help a little or a lot   “effects” vs “side” effects © Phillip C. DeMio, MD 2005

30. Transdermal DMSA in the treatment of the Autism Spectrum Disorders (ASD) © 5/06 Phillip C. DeMio, MD 320 Orchardview Ave, Suite 2 Seven Hills, Ohio 1 st Monday of the Month at Noon Radio Show on Autism One Radio, pdemio@autismone.com pdemio@autismone.com www.drdemio.com

31. What is DMSA? (2,3-meso- dimercaptosuccinic acid)  DMSA is a chelator  What is a chelator?  Chelators are substances that bind metals and extract them from the body (mostly into urine, stool and sweat).  The process is called chelation and can take anywhere from a few months to 2 years.

32. Why chelate in ASD? Toxicity in ASD  Mercury  Vaccines  Dental  Diet/other  Mercury is very toxic  Brain  Immune system  GI tract  Metabolism  Reproduction, skin, eye,…  “No matter what the cause…” (even when Hg and others are detected, controversy remains)

33. Toxicity in ASD cont.  Others Toxic Metals  Lead  Aluminum  Thallium  Tungsten  Arsenic  Antimony, Tin, Bismuth  They cause synergistic toxicity, in any known combination  If it weren’t for mercury, aluminum, vaccines, and dental work these would not be nearly the problem they are today.

34. Toxicity is ASD cont.  Chelation and minerals treat Hg toxicity  Simultaneous diagnostic information and treatment (essential and multiple toxic minerals)  Useful in treatment of ASD  Clean up the diet and the home  Other toxins  Testing is difficult  Treatment overlaps with that for heavy metals, especially glutathione  Clean up diet and home

35. Chelation  Based on history, exam, and testing  Part of a whole program  Must supplement  “Side effects”: metabolic, renal, skin, gi/fungal, cognitive  Musical chairs with sulfur  Topical vs. oral vs. IV; non-sulfur types  Requires follow-up with lab testing

36. A brief history of chelation and DMSA in treatment of poisoning with Hg and other metals  Why sulfur? (Mercaptans)  First Larger scale use of DMSA was to replace IV EDTA in lead toxicity with an oral treatment  DMSA was almost simultaneously found to be useful in toxicity with mercury and cadmium  Most of these cases were acute and subacute

37. History of Chelation and DMSA cont.  Recall the toxicity issues with heavy metals and ASD.  This is repeated acute exposure, but the result is a chronic problem  This requires ongoing treatment (slow and steady)  S. Cave and others: oral protocols

38. Oral DMSA protocols  Taste/swallowing issues  GI issues  “gi upset, irritation”, and other similar symptoms  Yeast!  Liver: why an oral issue? (less so with transdermal DMSA)  Labs  Follow metals  Hg and other toxic metals  Nutritional metals (are the result of ongoing treatment)  Liver, kidneys (not unheard of)

39. Why Transdermal DMSA?  It works!  Avoids oral aversions and many of the gi issues (it and eg. IV GSH can sometimes still stir up yeast)  Other compliance/convenience points (“asleep”, & etc,)  “timed-released” naturally

40. Transdermal DMSA cont.  Things to know:  Use gloves (eg. pregnant mom)  Odor  Rashes  Yeast  Metals moving  Can happen with any chelation (even oral/nasal/drops/IV/”natural”)

41. Transdermal DMSA cont.  Compounding R.Ph.  Invented by Lee-Silsby  85% vehicle  Varies more than oral products from one shop to another  Dr. DeMio’s rule  The pharmacist must talk to Dr. and parents  Stability/quality/experience

42. Transdermal DMSA: Other Considerations  Generally use with GSH or NAC (routes)  Brain Chelation: alpha-lipoic acid (topical), some others  Use in other disorders: ADHD, OCD, ODD, Asperger’s Syndrome, PDD(nos), RAD/adoptive issues, tics, apraxias, LD’s, shadow syndromes  Alzheimer’s Disease, MS, ALS, “neurodegenerative disorders”  Autoimmune: RA, SLE, IBD, severe “IBS,” severe eczema; severe allergy, autoimmunity, hypoimmunity  Cardiovascular Issues

43. Transdermal DMSA Follow- up: What do we look for?  Labs (metals, metabolic)  Clinical (ie, not just on paper)  “side” effects (clinical, labs)  Chelation is a big commitment (doctor, parent, patient)

44.  Time for Questions & Comments…