Transcript No Slide Title

AUTISM
CYMRU
By special arrangement with Joe Calzaghe
Paul Shattock University of Sunderland
The Use of Medications in the Treatment
of People with Autism Spectrum Disorders
Cardiff City Hall,
April 22nd 2008
In order to discuss the role of
interventions, including medications and
nutritional manipulations it is necessary
to have a theoretical model.
Such a model must be based on current
scientific and clinical observations.
Facts are “sacred”. Interpretations will
evolve with increased understanding.
Our current hypotheses may be wrong
but represent a “best fit” based on current
knowledge, understanding (and fashion).
The mechanisms described are
probably part, but not all, of the story.
For example: “opioid peptides” will affect
transmission in all the systems of the
central nervous system.
They will affect the immune system…
…..and the gastrointestinal system.
The guts, the nervous system and the
immune system are derived from the
same embryological tissues.
Unlike the residents of the this island,
they use the same “chemical” language.
This presentation is divided into two
parts (separated by light refreshment).
Part 1. The development of an overall
theoretical model.
Part 2. a) How current interventions fit
into the overall plan.
b) Some possibilities in various
stages of development and testing.
Four Pillars For Effective Support
1. Enhancement of Respect and Dignity
2. Biology, underlying forces
Must consider all these elements
For example:The child who lies over the chair all day.
Does anyone know a
gastro-enterologist,
anywhere in the UK, who
will investigate GI
problems in people with
Autism Spectrum
Disorders?
Must consider all these elements
For example:The child who lies over the chair all day.
The child who eats the bark from trees.
The child who loves salty things, the child
who detests or fears the colour orange.
Four Pillars For Effective Support
1. Enhancement of Respect and Dignity
2. Biology, underlying forces
3. Care:- Protection and Encouragement
4. Education
The pillars are of no use in isolation.
Remove any of the pillars and the
edifice collapses.
Baird G., Simonoff E., Pickles A., Chandler S.,
Loucas T., Meldrum D., Charman A. “Prevalence of
disorders of the autism spectrum in a population cohort of
children in South Thames: the Special Needs and Autism
Project (SNAP)” Lancet 368 210-215 (2006)
9-10 year old children in N.E. London Total
Prevalence of PDD
116.1 in 10,000
equivalent to 1:86 children
Estimates of 4:10,000 now 116:10,000.
Previously missed 97% ?
Suggest ratio of boys:girls now 8:1
ONE in 86 CHILDREN
is equivalent to
ONE in 50 BOYS
Aged 9-10 will include all spectrum
(NB This is NOT ADHD, Dyslexia and
other NeuroDiverse conditions)
Shattock Paul, Whiteley Paul,
Todd Lynda.
“Is there an Increasing Incidence
of Autism? evidence and
possible explanations.”
Consensus in Child Neurology
(Supplement of Journal of Child
Neurology) November 2002 29-34
ONE SIMPLIFIED ROUTE MAP TO AUTISM
Numerous Genes act separately or in combination
Sulphation
Methylation
Amino-Acids
e.g. Lactase
Variety of Symptoms of Autism
Are there
any Genes
Same Environment
– Different
diseases which are
either totally genetic
or totally
environmental in
origin?
Sunlight and Melanoma
Disease Threshold
Light
Skin
Environment
Genes
Dark
Skin
Are children with “ASDs” the
same all over the world?
If the environmental factors are
different, will people with autism
be the same as they used to be?
Are more children diagnosed now?
Have “borders” been extended?
Has earlier and more effective
intervention had an effect?
Are children with “ASDs”
the same all over the
world?
Bahrain and later onset of Symptoms
10 of 22 children (45%) showed no
signs until 20 months – mainly 24
months (probably an underestimate)
Koran requires breast feeding to
continue until age of 2.
Presentational differences: sociability?
Male – Female Ratios For ASDs
Usually accepted Figure 3-4 to 1
Recent Figures from UK 7-8 to 1
Data from Iran (In Press JADD) 1 to 1
Lack of male births in Northern Canada
Left handedness tripled in UK in 20 yrs
Intestinal Dysbioses
John Hunter (Cambridge)
Sophie Rosseneu (Royal Free,London)
Glen Gibson (Reading)
Use of antibiotics during pregnancy
and early infancy;
Caesarian births
Problems with establishment of
appropriate bacteria.
What environmental factors may be
involved with different individuals?
Diet – gluten, casein, corn, soya, GM products, MSG,
Aspartame, eggs, beef, avocado, allergenic foods.
Natal Issues – ultrasonics, cord cutting, Rhogam,
antibiotics, drugs, hypoxia/anoxia, infections vitamin K, folate,
alcohol, deficiencies of essential vitamins, minerals. fatty acids.
Exposures (especially during term) – pesticides,
PCBs, dioxins, bisphenols, mobile phones, heavy metals,
immune and endocrine modulators, infections, vaccines.
Physical Factors – Head trauma, gut or CNS ops,
Mental Stress – exacerbation of all symptoms
ONE SIMPLIFIED ROUTE MAP TO AUTISM
Numerous Genes act separately or in combination
Sulphation
Methylation
Amino-Acids
e.g. Lactase
Many Environmental Triggers varying with Location & History
Infection History
Vaccinations
Metals (Heavy and essential)
Pesticides
Gut Dysbioses
Dietary Status
????????????
Variety of Symptoms of Autism
ONE SIMPLIFIED ROUTE MAP TO AUTISM
Numerous Genes act separately or in combination
Sulphation
Methylation
Amino-Acids
e.g. Lactase
Many Environmental Triggers varying with Location & History
Infection History
Vaccinations
Metals (Heavy and essential)
Opioid Peptides
Pesticides
Gut Dysbioses
Carbohydrates
Dietary Status
????????????
Other Metabolites
Common Final Pathways
Neurotransmitters
Physical Structures
Variety of Symptoms of Autism
Genetic Fragility
Environmental Stressors - Cumulative.
Some dietary products that are more
common in a maritime diet.
Elements – Iodine, Selenium, Zinc
Fish Oils containing readily available
omega three fatty acids
Vitamins from fish – Vitamin A, D and
some B group (B12)
Human EVOLVED near the sea. Our
nutritional requirements assume that we
are still there.
What is Beta-Endorphin?
A peptide with morphine-like activity which
occurs naturally in certain brain areas
(endogenous morphine = endorphin)
Some reported effects of beta-endorphin
1. Altered Pain Sensitivity - (Antinociceptive
Effect)
Particularly at times of stress.
2. Altered EEG patterns - involvement
with epilepsy
3. Modification of sleep patterns
Some reported effects of beta-endorphin (cont)
4. Effects on Memory and Learning - Reward
leading to reinforcement and motivation
5. Decrease in Sociability
6. Involvement in Stereotypy/hyperactivity
7. Modification of Intake of Food and Drink
8. Constipation - “Abnormal” Poo
9. Regulation of Body Temperature
There are many other effects. This list is by
no means exhaustive
Hypotheses
1.
Peptides interfere with neurotransmission in all
the major systems of the C.N.S.
2.
These peptides are derived from the incomplete
digestion of food, principally gluten and casein,
in the Gastro-Intestinal Tract.
3.
These peptides cross into the bloodstream and
can enter the C.N.S. to exert their effects.
What are these biologically active compounds?
PEPTIDES
PROTEINS are made up of very long chains of AMINO-ACIDS.
During digestion, proteins are broken down
into short chains called PEPTIDES.
Typically, peptides contain 2-8 amino-acids,
but may be much larger (e.g. beta-endorphin)
Leu-ENKEPHALIN
(A naturally occurring neuropeptide)
Beta-CASOMORPHIN
Tyr-Gly-Gly-Phe-Leu
Human Tyr-Pro-Phe-Val-Glu-Pro-Ile
Bovine Tyr-Pro-Phe-Pro-Gly-Pro-Ile
These Peptides will affect transmission in the C.N.S.
and may therefore affect:Perception (Vision, Hearing, Taste, etc)
Cognition
Behaviours (e.g. Stereotypies)
Mood
Emotions
C.N.S. development (pruning of CNS)
(Immune System)
(Gastro Intestinal Tract)
THE TIMES – Monday 21st April, 2008
Prof Jeremy Nicholson – IC
in
“Nature”
“Metabolic profiling can tell us how specific aspects of
a person’s diet and how much they drink are
contributing to risks for certain diseases and these are
things that we can’t investigate by looking at a
person’s DNA.”
“They call such studies Metabolomics.”
“It seems we have been performing
metabolomic studies for almost 25 years.”
Control urine sample (no IAG present)
Standard urine sample for person with ASD
Beta casomorphin 1-7
Problems with casein
Urine profile: Male (born 1986), ASD
Behavioural regression following MMR vaccine
DYSLEXIA SAMPLES
FIRST DEGREE RELATIVES
Number with 20min peak
Mother
Father
Siblings
16/35
13/34
13/23
Percentage with 20min peak
46
42
56
trans – indolyl-3-acryloylglycine
IAG
Anderson RJ, Bendell DJ,
Garnett I, Groundwater PW,
Lough WJ, Mills MI, Savery D,
Shattock PEG. “Identification of
Indoly-3-Acryloyl Glycine in the
urine of people with autism.”
Journal of Pharmacy and
Pharmacology 54 (2) 295-298
(2002)
Alcorn A., Berney T., Bretherton K.,
Mills M., Savery D., Shattock P.
“Urinary Compounds in Autism”
Journal of Intellectual Disability
Research 48 (Part 3) 274-278
(March 2004)
CAVEAT………
Wright B et al. (Feb 25th 2005)
Developmental Medicine and Child
Neurology 47 (3) 190-192.
“Is the presence of urinary indolyl3-acryloyl glycine associated with
autism spectrum disorders?”
No!
(but…………)
Sulphation Problems in ASDs?
Circumstantial Evidence: Families with
Migraines? Baby jaundice? Rheumatoid
Arthritis? Other “sulphate” related issues.
P. SULPHATE
PARACETAMOL
P. GLUCURONIDE
ONE HOUR after
PARACETAMOL
determine ratio of
Paracetamol sulphate
-----------------------------Paracetamol glucuronide
WARING, R.H., NGONG, J., KLOVRZA, L.
University of Birmingham, School of Biochemistry,
UK
MEAN RATIO OF SULPHATE / GLUCURONIDE
AUTISM
0.87 +/- 0.67
CONTROL 2.09 +/- 0.65
(n = 46)
(n = 46) p < 0.005
PLASMA SULPHATE LEVELS
AUTISM
1.51 +/- 2.75 (n = 14)
CONTROL 8.30 +/- 5.40 (n = 14)
p < 0.001
Alberti A., Pirone P., Elia M., Waring R.,
Romano C.
“A sulphation deficit in autistic children:
a pilot study.”
Biological Psychiatry 8 420-424
(1999)
Sulphur Metabolism in Autism
Waring & Klovrza (2000)
Journal of Nutritional and Environmental Medicine 10, pp25-32
Results:
Age
Autism (n=232)
7.6 ± 2.4
Controls (n=68)
8.5 ± 3.7
Sulphite
Sulphate
106.9 ± 162.9*
6819.0 ± 6712.3*
2.1 ± 6.3
3030.8 ± 1461.0
Protein
103.2 + 89.9*
64.5 + 27.5
Thiosulphate 130.8 + 148.1*
18.6 + 25.0
Thiocyanate
44.0 + 101.0
6.4 + 16.9*
Anion excretion in nmol/ml. Mean+ SD* p<0.001 (Wilcoxon rank sum test)
Effects of lack of sulphating ability:1. Neurotransmitters not removed from system;
2. Toxic substances not removed from system OP pesticides? Metals? Bile pigments; Phenolics.
3. Mucus lining of GI tract becomes patchy increases permeability of intestines;
4. GAGs of GI wall less sulphated - increases
permeability of intestinal wall;
5. Loss of activity of certain hormones (CCK and
Gastrin?) and resulting malabsorptions;
6. Easing of access for Yeasts.
A
B
GUT
GUT
BLOOD
BLOOD
BRAIN
C
BRAIN
D
GUT
GUT
BLOOD
BLOOD
BRAIN
GUT
PERMEABILITY ?
GUT
PERMEABILITY ?
BLOOD-BRAINBARRIER PERMEABILITY ?
BRAIN
One, highly controversial, example
where a relationship between a
genetically determined fragility and
environmental factors is suggested
but not proven or disproven.
Possible relationship between MMR
vaccination and some regressive ASDs
Other environmental suboptimalities such
as giving the vaccine to a child who is
already sick (viral infections including
chicken pox (varicella). Role of Mercury?
Each
If
youGeneral
are in need
Practice
of areceives
good laugh……
almost
£8,000
Google
each my
yearname
for reaching
on the targets
internet.
for
MMR vaccination.
1. It seems I had my “snout in the
trough”
the MMR
case.
Who
hasduring
the vested
interest?
I hereby declare
my vested
Normally
one is only
paid forinterest
doing in that
over eight year
period not
I received
in total
something
one would
do anyway.
(according to newspaper reports) £8,000.
I DO NOT believe that GPs only vaccinate
Much
this was
etc).
for theofmoney
butexpenses
are there (travel
any other
Most
of my
was
not charged
products
forwork
which
similar
systemsfor.
apply?
IF (as current research indicates) ASDs
are occurring at a rate of 1 in 86 births
and the UK parents are telling the truth –
6.7% of ASDs are triggered by MMR:
ONE BRITISH CHILD IN 1,280 WILL BE
RENDERED AUTISTIC BY MMR VACCINE
IF the US parents are telling the truth and
50% of ASDs are triggered by MMR:
ONE American child in 200 will be
rendered “autistic” by MMR vaccination.
ONE AMERICAN BOY IN 140 WILL BE
“AUTISTIC” BY MMR VACCINATION
Some clinical signs that may correlate with
vaccine involvement in causation of autism.
1. Unusual sociability and friendliness.
2. Development of unusual thirst.
3. Abnormal Gait - flat-footed, padding;
- wide gait; toe walking.
4. Development of bowel problems
- constipation and diarrhoea.
It is recognised that all of the above occur in many children with autism but the
cluster of symptoms may be characteristic of this sub-group.
MUNCHAUSEN
SYNDROME
BY
PROXY
If you are in need of a good laugh……
Google my name on the internet.
1. It seems I had my “snout in the
trough” during the MMR case.
2. It is implied that I have faked my
qualifications (Dip.Ag.Vet.Pharm.)
I am the only academic in the UK with this
Qualification but rarely quote it at Autism
events because it is not relevant.
However…….it is now extremely relevant.
450
400
350
300
Transition to OP pesticides
ABBA win Eurovision
Song Contest
ARU
250
Taylor*5
200
NAS
Kaye*5
150
100
50
0
Year 1954 1957 1960 1963 1966 1969 1972 1975 1978 1981 1984 1987 1990 1993 1996 1999
of
birth
Other circumstantial evidence:1. Higher rate of ASDs in rural than urban
areas.
Budd R., “UK Autism Demographics”
Perspectives on Progress (2000) 207-214
“Maternal Residence Near Agricultural
Pesticide Applications and Autism Spectrum
Disorders Among Children in the California
Central Valley”
Roberts E.M., English P.B., Grether J.K., Windham G.C.,
Somberg L., Wolff C. National Institutes of Health, U.S. Dept of
Health and Human Services
July 2007
Environmental Health Perspectives http://dx.doi.org/
Reports increased incidence of ASDs the closer one
lives to fields sprayed with pesticides (certain
organochloride) and when the spraying occurs at time
of foetal CNS development. Suspicions about
Organophosphates but sample number too small?
Other circumstantial evidence:1. Higher rate of ASDs in rural than urban
areas.
Budd R.,
Roberts et al.
2. Behavioural effects of Malathion lotions for
treatment of headlice.
3. Seasonal Effects at “dipping” and “spraying”
time in rural communities.
4. Effects of accidental spraying.
5.Considerable anecdotal evidence for
effectiveness of organic diets.
6. Biochemical Plausibility. Many abnormalities
in ASDs explicable by OP involvement.
We have studied possible links between
organophosphate pesticides and ASDs
since 1995 – last publication was in 2002
Our data were “intriguing” but did
not make sense.
If it doesn’t make sense it is
probably important.
In 2007 there is more understanding and
our results have been reinterpreted and
makes sense.
Are they relevant?
Metabolism of phenylalanine in states
of hyperphenylalaninaemia
COOH
COOH
CH2
CH
NH
N-acetylphenylalanine
& other metaboiites
CH2
COCH3
dopa
decarboxylase
CH2
CH2
Phenylethanolamine
MAO
(Aldehyde)
NH2
Tyrosine
CH2COOH
Phenylketonuria
NH2
Phenylalanine
p-hydroxyphenol
pyruvate oxidase
dopamine
beta-hydroxylase
OH
X
CH
OH
transaminase
CH2
CH2
NH2
Phenylethylamine
o-hydroxyphenolacetate
CH2
CO
COOH
aromatic alpha-ketoacid
reductase
OH
Phenylpyruvate
MAO
CH2
Phenylacetyl - CoA
(Aldehyde)
CH
COOH
Phenyllactate
OH
CH2 COOH
CH
COOH
Phenylacetate
CH2
CO
NH
CH
CH2
CH2
COOH
Mandelate
Phenylacetylglutamine
CO
NH2
Some elements of the Metabolism of Tryptophan
3-Indole Acetic Acid (3-IAA)
Indole and Indican
3-Indole Propionic Acid
3-Indole Pyruvic Acid
Kynurenine and
derivatives
TRYPTOPHAN
3-Indole Acrylic Acid
(IAcrA)
(tryptophan hydroxylase)
5-Hydroxy Tryptophan
Organophosphate
inhibition
(5-Hydroxytryptophan decarboxylase)
3-Indolyl Acryloyl Glycine
5-Hydroxy Tryptamine
(IAG)
(5-HT; Serotonin)
Melatonin
Bufotenin
5-Hydroxy Indole Acetic Acid (5-HIAA)
How do organophosphates kill?
As a nerve impulse passes from one nerve
to another OR from a nerve to a muscle a
chemical transmitter is involved.
Very often, this transmitter is Acetylcholine
Acetycholine is broken down, immediately,
by choline-esterase enzymes.
OPs have anticholine-esterase activity.
Acetylcholine persists so nerve impulse or
muscle contraction continues – paralysis.
How do OPs become active?
The parent molecule (as spread on crops)
has little anticholinesterase activity. Bulk of
Activity resides in metabolites.
Malathion
Malaoxon
Diazinon
Diazoxon
Parathion
Paraoxon
Fat soluble OPs are made water soluble
and can become 1000 times more active.
This is the first stage in removal of toxins.
Metabolism of OP Insecticides
Parent OP
(Malathion, Diazinon,)
Cytochrome P450 system
Active
water soluble
–oxon form
(Maloxon, Diazoxon)
Paraoxonase enzymes
Excreted Metabolites
Metabolism of OP Insecticides
Parent OPs
Malathion and Diazinon
Thioates
Cytochrome P450 system especially 1A2 and 3A4
1A2 and 3A4 are Suicide Enzymes
when reacting with Thioates
Other substrates for 12A and 3A4 will
persist – Testosterone and Estradiol
Elevated Testosterone in Amniotic Fluid
of Babies who develop ASD (Baron-Cohen)
D’Amelio M., Ricci I., Sacco R., D’Aguma L.,
Muscarella LA., Guarniri V., Militerni R., Bravaccio
C., Elia M., Schneider C., Melmed R., Trillo S.,
Pascucci T., Puglisi-Allegra S/. Reichelt K-L.,
Macciardi JJA., Persico AM.
“Paraoxanase
(PON1) gene variants
are associated with autism in North
America but not in Italy: possible
regional specificity in gene –
environment interactions”
Molecular Psychiatry 10 1006-1016
(2005)
SNP Genotyping for the PON1 Polymorphism G(192)A
Homozygous Mother
Normal Allele
Mutant Allele
Homozygous Father
Normal Allele
Heterozygous Child
Normal Allele
Mutant Allele
Mutant Allele
Some astonishing slides taken from
the presentation of Prof Clement
Furlong, University of Washington,
Seattle.
http://www.gs.washington.edu/faculty/furlong.htm
A “must read” for anyone interested
in this field
OPs & Blood Brain Barrier Permeability
1. Hypotheses involving Indole Acrylic Acid.
2. Studies demonstrating increased BBB
permeability with OPs. (Sinha C., 2003,
Damani K., 2004, Jones K, Abou-Donia M, 2004)
3. Pyridostygmine Bromide (PB) and GWS.
4. “Opportunist” xenobiotics and organisms
a) Prions and “Mad Cow Disease” ??
b) Paraquat and Parkinson’s Disease?
c) Peptides from food
OPs & Blood Brain Barrier Permeability
Parran DK., Magnin G., Li W., Jortner BS., Ehrich
M. “Chlorpyrifos alters functional integrity and
structure of an in vitro BBB model”
NeuroToxicology 26 77-88 (2005)
Song X., Pope C., Murphy R., Lal B., Bressler B.
“Interactive effects of paraoxon and
pyridostigmine on blood-brain barrier integrity and
cholinergic toxicity” Toxicol. Sci. 78 241-247
(2004)
Paraquat
1-methyl-4-phenylpyridinium (MPP+)
Paraquat would not normally be expected to
cross the blood brain barrier. Would this
change if OPs had increased permeability?
Prior studies have shown that people with
Parkinson's disease are over twice as
likely to report being expose to pesticides
as people without the disease, but few
studies have looked at this association in
people from the same family or have
assessed associations between specific
classes of pesticides and Parkinson's
disease.
Nature – Neuroscience 2008 via Reuters and BBC
Website 18th April 2008
ARE THERE OTHER SIMILAR
COMPOUNDS INVOLVED
a) Lubricant additives, especially
in planes, affect cabin crews.
b) Glyphosate (Roundup)
herbicide – greatly increased
levels in GM crops.
Overlapping of Function
Systems are designed for particular
function but have other abilities.
If one system is suboptimal it is not fatal
as others take over the function.
Pressure on any part of system through
too much stressor or too little activity
puts stress on the whole redox system.
Benefits may not be directly related to
known effects.
Prof Jill James, University of Arkansas
Experimental Biology Conference, San
Diego March 2005.
“Levels of the antioxidant “Glutathione”
are reduced in the blood of children with
ASDs. “When glutathione is less
available, then it is easier for things to get
out of balance and the free radicals can
cause more damage. ……children with
autism would be less able to detoxify
heavy metals.”
S
u
Spectrum of Treatment Modalities
p
p Psychotherapy and Counselling
Exclusion Diets
o
r
Behavioural
Alteration of
t
Approaches
“Environment”
i
v
e
S
o
c
Traditional
i
Biomedical
Teaching
e
Approaches
Detox.
t
Support
y Sensory & Cognitive
Programmes
Symptomatic Medication
P
o
l
i
t
i
c
a
l
D
e
c
i
s
i
o
n
“A new scientific truth does not
triumph by convincing its
opponents and making them see
the light, but rather because its
opponents eventually die and a
new generation grows up that is
familiar with it.”
Max Planck - 1902
Press Release from the American
Academy of Pediatrics April1st 2008
“Most recently, the AAP met with representatives
of Defeat Autism Now!...in an effort to facilitate
communication between pediatricians, parents
and researchers about the diagnosis and
treatment of children with autism. All advocates
for these children agee that further research is
needed regarding causes as well as safe and
effctive treatment.”
We are full of hope that this is the beginning of a thoughtfull partnership that will further
explore factors that might cause or contribute to autism, as well as examine safe and
effective treatment approaches for families coping with this condition.”
Press Release from the American
Academy of Pediatrics April1st 2008
“We are full of hope that this is the
beginning of a thoughtful partnership that
will further explore factors that might cause
or contribute to autism, as well as examine
safe and effective treatment approaches for
families coping with this condition.”
Stan Kurtz – representative of DAN!
Any Chance of it happening here? PS
THE SUNDERLAND PROTOCOL
(Shattock & Whiteley, 2000)
“CEASEFIRE” - Remove source of bullets
1. CASEIN
- 3 weeks
2. GLUTEN
- 3 months
PRELIMINARY AGREEMENT
3. OTHER FOODS - Food diary (Corn; Soya; Tomatoes; Avocado; Beef et al)
4. TESTING
- Vitamins, Minerals, Amino Acids, Allergies (IgG, IgE)
Supplement as appropriate:
Zn, Ca, Mg, Mb, A, C, B1, B3, B6
5. PARASITIC ORGANISMS - Yeasts, Others
ACTIVE RECONSTRUCTION
6. SULPHATION ISSUES - Epsom Salts (Internal/External), MSM
7. ENZYME ACTIVITY - Betaine Hydrochloride
8. FATTY ACIDS - Evening Primrose Oil, Fish Oils,Cod Liver Oil (Vit. A), Flax Seed
9. L-GLUTAMINE - Correct Imbalance, Intestinal Nutrient
10. ENZYME SUPPLEMENTATION - Bromelain, Seren-Aid, EnZymAid.
_______________________________________________________________________
11. 5-HYDROXY TRYPTOPHAN (5-HTP) 14. MEGADOSE B6 & Mg
12. PIGMENT-FREE
15. DIMETHYLGLYCINE (DMG)
13. SALICYLATE-FREE
16. SPECIFIC CARBOHYDRATE DIET
LIST OF DRUGS DEMONSTRATED
AS BEING EFFECTIVE AND SAFE
IN THE TREATMENT OF AUTISM
May 2005. FDA fails to
approve Risperidone for use
in Autism .
Approved in September
2006.
The Sunderland Protocol
A logical system for the implementation
of biomedical interventions for people
with autism and related disorders.
The protocol is divided into three sections and is based loosely
upon the “Northern Ireland Peace Process”
1. The Ceasefire - removal of guns and bullets;
2. The Preliminary Agreement
- and analysis of underlying problems;
3. Active Reconstruction - permanent resolution.
Before you start……………….
1. Read and understand;
2. Obtain professional support;
3. Consider known conditions Coeliac Disease and amino-acids;
4. Take a good, balanced,(GF/CF)
vitamin and mineral supplement.
Each therapy must be seen as a part of
an overall treatment programme.
These biomedical interventions are not
alternatives to an educational
programme - they are complementary.
Each intervention must be seen as a
time limited experiment for that person.
Only if the benefits outweigh the
problems - continue. If not - stop it.
Be prepared to revisit failed interventions..
“THE CEASEFIRE”
1. Remove Casein Derivatives;
three weeks and assess situation.
Milk from Cows is wonderful
food for Baby Cows
….or for genetically modified
humans – those with thick
leather skins and horns…….
Lucarelli et al (1995)
- Effect of casein-free diet (alone) (n=36; age 8-13 yrs)
+ control group (n=20)
- Blind casein-challenge (placebo vs. casein capsules)
- IgE, IgA, IgM, IgG antibodies to food antigens (pre-diet)
- Behaviour Summarised Evaluation (BSE)
Results:
Significantly elevated levels of:
- IgA specific antibodies to casein, ß-lactoglobulin
- IgM & IgG antibodies to casein
- IgM to lactalbumin
Significantly changes to BSE after 8 wks of diet
(autistic isolation, verbal communication, cognition)
* Changes to BSE following casein-challenge
Food ain’t what it used to be.
BUT
Are there other peptide sequences with opioid or other
biological activity?
Consider Organic Production!
Consider avoidance of “Gluten” containing feedstuffs for
cattle.
Must be seen as part of an overall strategy for individuals.
We need a quick, cheap and cheerful, pilot study
(Suggest Sunderland (UK) and Phoenix (USA))
1) Different Breeds (species);
2) Pasteurized & homogenized;
3) Days old (at best);
4) Cows fed on different food –
different fatty acid component;
5) US only (packed with
hormones and antibiotics).
Milk
“THE CEASEFIRE”
1. Remove Casein Derivatives;
three weeks and assess situation.
2. Remove Gluten and derivatives;
three months (at least) - assess.
Separate elements to minimise side effects;
Preliminary stage - remove obvious “bullets”.
Some transient negative effects following the removal of
gluten and/or casein from the diet of people with autism
These effects are variable in extent but experience suggests
that they may be more apparent in younger and smaller children
- Anxiety
- Clinginess
- Crying and general whinginess
- Staring into space
- Marked decrease in movement / dizziness
- Increased frequency in urination / defaecation
- Flu-type symptoms
Diet = did have a positive effect on behaviour and cognitive functioning of most participants
although: there was variability in each child’s response to it
Gluten free group: Primary changes in behaviour
• Increased attention and concentration
• Increased awareness of self and surroundings
• More calm and settled
• Decreases in hetero and/or auto aggression episodes
• Improved sleeping patterns
EPILEPSY
a Warning!
PRELIMINARY AGREEMENT
3. Keep a food diary - Idiosyncratic effects
(Corn; soya; eggs; beef; tomato; avocado.)
4. Testing - vitamins and minerals;
- allergies (IgE; IgG; others?)
supplement or remove as appropriate.
5. Parasitic organisms;
- consider yeasts; protozoa; worms.
ACTIVE
ACTIVERECONSTRUCTION
RECONSTRUCTIONPROCESS
PROCESS
6. Sulphation Issues - Epsom salts; MSM.
ACTIVE
ACTIVERECONSTRUCTION
RECONSTRUCTIONPROCESS
PROCESS
6. Sulphation Issues - Epsom salts; MSM.
7. Enzyme activity - Betaine Hydrochloride.
8. Fatty Acids - a) evening primrose, b) fish
oils; c) cod liver oil (Vit A); d) flax oil.
Fatty Acid Metabolism
Omega 3
Omega 6
Alpha-linolenic acid (ALA)
EicosaPentanoic Acid (EPA)
DecaHexanoic Acid (DHA)
Anti-Inflammatory
Linoleic Acid (LA)
Arachidonic Acid (AA)
Inflammatory
EICOSANOIDS
ACTIVE
ACTIVERECONSTRUCTION
RECONSTRUCTIONPROCESS
PROCESS
6. Sulphation Issues - Epsom salts; MSM.
7. Enzyme activity - Betaine Hydrochloride.
8. Fatty Acids - a) evening primrose, b) fish
oils; c) cod liver oil (Vit A); d) flax oil.
9. L-Glutamine;
correct imbalance; nourish intestines.
10. Enzyme supplementation - bromelain;
SerenAid; EnzymeAid; Peptizyde
ACTIVE RECONSTRUCTION PROCESS
11. 5-Hydroxy Tryptophan (5HTP);
- to bridge the missing stage.
Importance of Vitamin B6 (Pyridoxine)
Role of Pyridoxyl-5-Phosphate but it can’t cross the blood brain barrier
ACTIVE RECONSTRUCTION PROCESS
11. 5-Hydroxy Tryptophan (5HTP);
- to bridge the missing stage.
12. Pigment-free diet (sulphation issues).
13. Salicylate-free diet;
- prostaglandin inhibition.
14. Megadose B6.
15. DiMethyl Glycine (DMG).
16. Specific Carbohydrate Diet.
Diagrammatic
representation of a
dopaminergic synapse
Tyrosine
DOPA
Inhibition of DOPA
Inhibition of Tyrosine
formation
Hydroxylase
Key
Dopamine
Stimulation of
Decreased release
= D1 receptor D2 receptors
of Dopamine
= D2 receptor
= Dopamine
The same principles apply with all
the main neurotransmitter systems
of the Central Nervous System.
There are “pre-synaptic receptors”
which are stimulated by opioid peptides.
Thus, opioid peptides regulate transmission
in all the systems of the CNS.
They act as “Neuro-regulators” rather
than direct “neurotransmitters”.
Many drugs have a preference for one
type of receptor over the other.
For example: Risperidone blocks D2
receptors first. At higher concentrations it
will block D1 receptors.
So at Low concentrations there will be an
INCREASE in transmission and at higher
concentrations a DECREASE in
transmission of Dopamine
Many drugs have a preference for one
type of receptor over the other.
For example: Risperidone blocks
5HT1b receptors first. At higher
concentrations it blocks
5HT1a receptors.
So at Low concentrations there will be an
INCREASE in transmission and at higher
concentrations a DECREASE in
transmission of Serotonin (5HT)
Bell Shaped Dose Response Curve (as seen with Self
Injurious Behaviour and Sulpiride (D2 > D1 Antagonist)
I
n
c
i
d
e
n
c
e
and with Naltrexone
o
f
S
I
B
Dose of Medication
We will get a “bell shaped
dose-response curve”.
The “Goldilocks Effect”
The ideal “dose” will vary
between individuals and will
depend upon the target
symptom.
Nota Bene
There are at least 15 “subtypes” of
Serotonin receptors
There are at least 8 “subtypes” of
Dopamine Receptors
As well as affecting these receptors,there
are at least 6 opioid receptor “subtypes”
….& receptors for GABA, Acetyl Choline,
Adrenalin, Noradrenalin, Amino-Acids such
as glycine and glutamine and many peptides
Cholinergic systems stimulate movement
Dopamine system stimulates or depresses
cholinergic system (on concentration)
GABA system stimulates or depresses
dopamine system (on concentration)
Endogenous peptides regulate all of above
to produce
a balanced, homeostatic system
Exogenous substances (peptides and
drugs) will disrupt or alter the balance.
Up regulation and down regulation
of receptors - depends upon
degree of stimulation.
If greater stimulation - numbers of
receptors or sensitivity will decrease.
If decreased stimulation numbers of receptors or
sensitivity will increase
We are still reliant upon
empirical, as far as
possible, evidence
based medicines.
The dose for children with
ASDs will not be the same as
for other children because:Transmission is different in ASD
People with ASDs do not
metabolise drugs as efficiently
as Controls. Drugs persist for
longer.
The Choice of Medication
1.Drug,
2.Route of Administration,
3.Evidence of efficacy and safety
in ASDs – Professional
support.
Dosage of Medication
1. May not be the same as for
“Neurotypicals” or other disorders.
2. Persistence due to deficiencies in
sulphation, methylation etc.
3. Titration – start (very) low and
increase slowly……. (5 x Half Life.)
4. Liquid Formulations (personalised)
-use of percutaneals or sublinguals?
Following Instructions
1. Take X times a day! spread out over
the 24 hours.
(Not at midnight)
2. Other instructions: Avoid Milk; Before
or After Meals. INSTRUCTIONS – NOT
JUST ADVICE!
3. In the UK estimated that 13% of
medicines taken as directed. No wonder
they don’t work!
Take with Water
The biggest cause of refusals to take
medication – resolution is simple!
Oesophagus is not solid tube – peristalsis
is required to move tablet or capsule.
Take with a minimum of 100ml of water.
The oesophagus is probably inflamed and
very sensitive in any case.
Would take take something causing pain?
Drug Interactions
Computers in Pharmacies should keep
records of all medications including
herbals and “Over the Counter” products.
Any adverse event must be recorded.
Specific (idiosyncratic) sensitivities occur.
Look for drugs with similar actions; drugs with opposite actions;
drugs which are “detoxified from the body using the same
mechanisms; drugs which physically react in the stomach;
drugs which react with alcohol or aspirin; drugs with complex
interactions (antibiotics and birth control pills) etc etc.
Side Effects
The drug without side-effects does
not exist. No side-effects means no
activity.
A problem for Physicians and Pharmacists
– How much to say?
Carers – Parents, staff, professionals
must be aware of the possibilities and
actively look for them.
Some Examples of Side-effects
Antibiotics
Effects on intestinal bacteria and
appearance of resistant types and yeasts
Look for changes in intestinal function –
(diarrhoea) and behaviour (positive or
negative).
Use in short courses;
Consider introduction of probiotics.
Some Examples of Side-effects
Diuretics to reduce blood pressure
Effects on water and potassium content.
Look for dryness of the mouth – drinking
more fluids; tiredness, nausea, irregular
heartbeat, mood or mental changes.
Reduce dose? Supplement Potassium
salts,
Some Examples of Side-effects
Newer Neuroleptics (Risperidone, Olanzepine)
Classic stereotypies, constant
movements, dyskinesias (permanent).
Acquired Obesity is very common.
Possibility of Diabetes.
Use in short courses and reduce dose
when feasible (withdrawal dyskinesias?)
Constant vigilance!
Carers should look for and report
Increased restlessness or drowsiness
Skin rashes (of any sort)
If any rapid and
High temperature
sudden
Weakness
Mood Changes/Confusion/Dizziness
changes occur
Dryness of the mouth or thirst
THINK DRUG!
Unusual colour or smell to the urine
Pains Persistent Cough
As populations age…….
What was an appropriate dose becomes
an overdose……..because:The individual’s size decreases.
Liver and kidneys, responsible for
breakdown and removal, lose efficiency.
Fat to muscle ratio decreases – less
drug stored in fat. More is available and
circulating in blood stream.
S
u
Spectrum of Treatment Modalities
p
p Psychotherapy and Counselling
Exclusion Diets
o
REGULATORY
r
Behavioural
Alteration of
t
Approaches
DRUGS “Environment”
i
v
e
S
o
c
Traditional
i
Biomedical
Teaching
e
Approaches
Detox.
t
Support
y Sensory & Cognitive
Programmes
Symptomatic Medication
P
o
l
i
t
i
c
a
l
D
e
c
i
s
i
o
n
Some Potentially Useful Medications
which with “regulatory” effects
1. Piogliazone (Actos) (30-60mg/day)
Currently used for treatment of diabetes
Employed on account of potentially
beneficial anti-inflammatory and
immune modulating effects.
Boris M., Kaiser C. et al. “Effects on behavioral symptoms
in autistic children” Journal of Neuroinflammation 4 (3) 2007
Comments – Encouraging results in children aged 3-17 who
had not responded to biomedical interventions. Preliminary
study – better outcome measurements vital.
Some Potentially Useful Medications
which with “regulatory” effects
2. Anti-testosterone Drug - Leuprolide
Acetate (Lupron).
Employed on account of possibility of
reducing effects of Mercury and belief
that Mercury is the cause of autism.
Interesting overlap with “Male Brain”.
Geier D and Geier M. published report in “Medical
Hypotheses” only.
Potential for Side-Effects seriously limit uptake and use by
physicians. Suggest Serious Caution!
Some Potentially Useful Medications
which with “regulatory” effects
3. Spironolactone Once extensively
used to control high blood pressure.
Employed for anti-inflammatory and
immunomodulatory effects in brain and
guts. Also anti androgenic effects.
Bradstreet JJ., Smith S., Granpeesheh D., El-Dahr JM.,
Rossignon D. “Spironoloctone might be a desirable
immunologic and hormonal intervention in autism spectrum
disorders” Medical Hypotheses (2006)…pp xxxx
Comments: Very plausible but largely anecdotal at present
Worth a formal trial under very controlled conditions.
Some Potentially Useful Medications
which with “regulatory” effects
4. Very low dose Naltrexone (LDN)
An old friend revisited.
Formerly employed (at low doses) to
inhibit opioid activity. Reintroduced as
immunomodulator at VERY low doses.
Jacquelyn McCandless involved in current trials.
Publications rather speculative at present.
Comments – Encouraging results with diabetes (published)
and other auto-immune disorders. Important studies v AIDS
in Africa. (Right product formerly used for wrong reasons?)
Epsom Salts in Bathwater
Some drugs (Tylenol and some
antipsychotics) rely upon sulphation
for metabolism and removal.
Existing levels of medications can be
reduced and effectiveness reduced.
Side-effects could be re-appearance of
symptoms in original or modified form.
There is no such thing as an
effective intervention that does not
have a potential for side-effects.
Whenever there is a change in health,
behaviour, or well-being... think “drug”
…..even an apparently innocuous
intervention can result in unpredicted
consequences – sometimes related to
existing interventions.
Do we affect the rate of breakdown of
drugs with biomedical interventions?
By encouraging sulphation with
Epsom Salts and MSM?
By encouraging methylation with B12,
Betaine, Folic Acid?
By introduction of other foods or
drugs using same breakdown paths.
Available levels may change with
sweating.
Genes can be switched on (or
off) by environmental elements:Methylation
Phosphation
Propionic Acid (from intestinal bacteria?)
Gradual filling in the gaps in evidence.
Practice has preceded evidence.
Current (definitive) trials of gluten and
casein free diets (in Denmark).
Trials of Omega 3 containing Fish
Oils. Takes longer to produce
significant results. Some non
responders (or negative responders).
The Rising Sun Coal Mine - Newcastle
Mining since 1650. Extremely polluted
with heavy metals and other chemicals.
A school was recently opened on this site
Rising Sun School for Autistic Children
Paul Shattock
Autism Research Unit,
School of Health Sciences,
University of Sunderland,
SUNDERLAND SR2 7EE
Tel: 0191 510 8922
Fax: 0191 567 0420
[email protected]
http://osiris.sunderland.ac.uk/autism/