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

 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
 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
Co nsi der White Blo od
Ce lls a s a n Or gan
 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
What Happens in K ids wit h
ASD w ho have A bnormal T h-
1/ Th-2 Funct ion?
 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

 Abn ormal Th- 1/ Th- 2
Functi on,
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”)
 Acto s’s Ef fects o n
Lymp hocyt es
 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.
 Goals in th e Use o f
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
Pr agmatics of Ac tos i n
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!
Pr agmatics of Ac tos i n
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)
Pr agmatics of Ac tos i n
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
Pr agmatics of Ac tos i n
ASD : a Few Co mme nts
 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.
Pr agmatics of Ac tos i n
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!
Low Dose Na lt re xone
in the Tr eatm ent o f
Au tism Sp ectru m
Diso rders
Phillip C. DeMio, MD
320 Orchardview Ave.
Suite 2
Seven Hills, OH 44131
216-901-0441
www.drdemio.com

© Phillip C. DeMio, MD 2005

Low Do se Naltr exone
(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

Low Dose Nal trexone
(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

Opi ate Pe pt ides ,
Nal trexone, and the
Immune Connecti on
 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
Imm une Co nnectio n
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

Low-Do se Connectio n
 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

Low-Do se Connectio n,
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

Low-Do se Connectio n,
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
LDN in Cli nic al u se fo r
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

Cli nical u se , 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

Cli nical 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

Cli nical 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
What to Ex pect in
Cli nical 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

Ot her Cli nic al I ssues
 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
Re visit ing t he Do se
 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
LDN Co nclu sio n
 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

Tr ansd er mal DM SA
in the tr eatment of
the A utism
Sp ectr um Diso r der s
(ASD)
© 5/06 Phillip C. DeMio, MD
320 Orchardview Ave, Suite 2
Seven Hills, Ohio
1st Monday of the Month at Noon Radio Show on Autism One
Radio, pdemio@autismone.com
www.drdemio.com
What is DMS A? (2, 3-
meso -di mer captosucci nic
aci d)
 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.
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)
To xicit y in ASD c ont.
 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.
 To xicity is ASD c ont.
 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
Ch elatio n
 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
A bri ef hi story of
chel ati on a nd DMSA in
treat ment of poi soni ng
with Hg and other met als
 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
Hi story o f Chel ati on and
DMS A co nt.
 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
 Ora l 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)
Why Tra nsd ermal
DM SA?
 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
Tr ansderma l 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”)
Tr ansderma l 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
Transdermal DMSA:
Other Co nsid erati ons
 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
Transdermal DMSA
Fol low -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)
 Time for Questions & Comments…