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Showing posts with label clonidine. Show all posts
Showing posts with label clonidine. Show all posts

Friday 9 December 2016

Glutamate Inhibitors to Treat Some Autism and ADHD




 A festive queue at the pharmacy for Glutamate Inhibitors


We have now established that much autism and indeed other disorders, from Down Syndrome to Schizophrenia, features a degree of excitatory/inhibitory (E/I) imbalance.

It is very likely that there are multiple underlying causes for this and so there may be multiple treatments.  We can even potentially use a treatment for one cause (ALS) to improve outcomes in others.  So we can (partially) solve a problem without fully understanding its origin, as frequently is the case in biology.

An E/I imbalance might cause anxiety in the adult with Asperger (treatable with Baclofen), contribute to MR/ID in the child with Down Syndrome and contribute to seizures and cognitive loss in someone with severe autism.

Very interestingly in the comments to a previous post, Agnieszka has pointed out why common penicillin type antibiotics (beta-lactams) improve many people’s autism.  This is very common observation and our other guest blogger Seth Bittker found the same in his son. Nat’s guest speaker at her autism conference also found this in his son.

The Glutamate Transporter 1 (GLT-1) is a protein that in humans is encoded by the SLC1A2 gene.   It is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. Glutamate is an excitatory neurotransmitter, so it encourages neurons to fire.

By upregulating the GLT1 transporter you increase the inactivation of glutamate and so shift the Excitatory/Inhibitory balance towards inhibitory.

Agnieszka highlighted this paper from Johns Hopkins:-




Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2), the physiologically dominant astroglial protein. In spite of its critical importance in normal and abnormal synaptic activity, no practical pharmaceutical can positively modulate this protein. Animal studies show that the protein is important for normal excitatory synaptic transmission, while its dysfunction is implicated in acute and chronic neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, brain tumours and epilepsy. Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, we discovered that many beta-lactam antibiotics are potent stimulators of GLT1 expression. Furthermore, this action appears to be mediated through increased transcription of the GLT1 gene. beta-Lactams and various semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial synthetic pathways. When delivered to animals, the beta-lactam ceftriaxone increased both brain expression of GLT1 and its biochemical and functional activity. Glutamate transporters are important in preventing glutamate neurotoxicity. Ceftriaxone was neuroprotective in vitro when used in models of ischaemic injury and motor neuron degeneration, both based in part on glutamate toxicity. When used in an animal model of the fatal disease ALS, the drug delayed loss of neurons and muscle strength, and increased mouse survival. Thus these studies provide a class of potential neurotherapeutics that act to modulate the expression of glutamate neurotransmitter transporters via gene activation.



It actually gets more interesting and relevant to treatment.

Mutations in SLC1A2 which decrease expression of the GLT-1 protein are associated with amyotrophic lateral sclerosis (ALS). 

The drug riluzole approved for the treatment of ALS upregulates GLT-1.

This would suggest that Agnieszka, Seth and John Rodakis might want to pay a visit to the pharmacy and pick up some riluzole.  It is certainly worth investigating.

I did check and there is even a trial on Riluzole in autism and evidence of existing off-label use.  They have not of course made Agnieszka’s connection; they seem to be just trying it because nothing else seems to help. That really is trial and error and makes this blog look positively scientific by comparison.
Drug: Riluzole

50mg once daily (QD) for 12 weeks for participants 6-11 years old; 50mg twice daily (BID) for 12 weeks for participants 12-17 years old





A reformulation of riluzole that originated at Yale University and is known by the code name BHV-0223 is under development for the treatment of generalized anxiety disorder and mood disorders  by Biohaven Pharmaceuticals.

  
Anyway, are there any other ways to inhibit Glutamate?

Yes, our reader Valentine just stumbled on one, tizanidine, but there are at least two others. 


α2 adrenergic agonists

Three other known inhibitors of glutamate happen to be α2 adrenergic agonists

·        Clonidine

·        Guanfacine

·        Tizanidine


All three of the above are already used in ADHD and sometimes in autism, but not to reduce glutamate.

I wrote a post about Clonidine use in autism a long time ago.



Guanfacine is an ADHD drug known to inhibit glutamate release.



At five sites, children with ASD and moderate to severe hyperactivity were either given guanfacine or a placebo tablet for eight weeks, in a randomized and double-blind clinical trial. The research team collected information from parents and measured each child’s overall response. After eight weeks of treatment, extended release guanfacine was superior to placebo for decreasing hyperactivity and impulsiveness.


Our reader Valentina seems to have stumbled upon tizanidine, but finds it helpful for her son. Tizanidine is a α2 adrenergic agonists but also inhibits glutamate.  It is one of the drugs used off-label by Dr Chez in ADHD and autism




CONCLUSION:


The overall safety of tizanidine in the pediatric group appeared good; however, the adverse event profile differed from that in adults. This difference most likely reflects the off-label use of tizanidine as adjunctive treatment for attention disorders and autism. The frequency and nature of adverse events in adults were consistent with the tizanidine prescribing information as reported for its approved indication, i.e. management of spasticity.



Conclusion

Ideally you would have a comparison of the four drugs:


·        Riluzole

·        Tizanidine

·        Clonidine

·        Guanfacine


We know clonidine is not an autism wonder drug, but then what is?

I think Riluzole is likely to be a good one, but very likely what works best will vary from person to person.

Perhaps a positive response to beta-lactam (penicillin) antibiotics is a biomarker for people who will respond to Riluzole? It should be.







Thursday 14 November 2013

Clonidine, ADHD and Autism


Clonidine has been used for more than half a century as an antihypertensive drug, to lower blood pressure.

It later found favour as a treatment for ADHD, drug withdrawal treatment, tobacco withdrawal treatment and a wide range of psychiatric disorders.  Off label usage of Clonidine includes autism.

Until recently it appeared to researchers to be a centrally acting α2 adrenergic agonist, but recent research indicates than instead it is a centrally as an imidazoline receptor agonist.  This would account for its actions other than lowering blood pressure. Maybe it is both.  The good thing is that it is centrally acting (i.e. acting on the brain and the CNS) and it does appear to work. 

Adrenergic Agonist
As a centrally-acting α-adrenergic receptor agonist, Clonidine has more affinity for α2 than α1. It selectively stimulates receptors in the brain that monitor catecholamine (epinephrine, norepinephrine and dopamine) levels in the blood. These receptors close a negative feedback loop that begins with descending sympathetic nerves from the brain that controls the production of catecholamines.  By fooling the brain into believing that catecholamine levels are higher than they really are, clonidine causes the brain to reduce its signals to the adrenal medulla, which in turn lowers catecholamine production and blood levels. The result is a lowered heart rate and blood pressure.

Imidazoline Receptors
There are three classes of imidazoline receptors:
  • I1 receptor – mediates the sympatho-inhibitory actions of imidazolines to lower blood pressure
  • I2 receptor – an allosteric binding site of monoamine oxidase and is involved in pain modulation and neuroprotection.
  • I3 receptor – regulates insulin secretion from pancreatic beta cells

L-Monoamine oxidases (MAO)
MAOs are enzymes that act as catalysts.  There are two types of MAO: MAO-A and MAO-B
MAO- A is an enzyme that degrades amine neurotransmitters such as dopamine (DA), norepinephrine (NE), and serotonin (5-HT).

MAO-B is an enzyme that catalyzes the oxidation of arylalkylamine neurotransmitters, including dopamine (DA).
The differences between the selectivity of the two enzymes are utilized clinically.  MAO- A inhibitors have been used in the treatment of depression, and MAO-B inhibitors are used in the treatment of Parkinson's disease

Selective MAO-B inhibitors preferentially inhibit MAO-B, which mostly metabolizes DA. If MAO-B is inhibited, then more DA is available for proper neuronal function, especially in Parkinson's Disease. 

Clinical significance
Because of the vital role that MAOs play in the inactivation of neurotransmitters, MAO dysfunction (too much or too little MAO activity) is thought to be responsible for a number of psychiatric and neurological disorders. For example, unusually high or low levels of MAOs in the body have been associated with schizophrenia, depression, attention deficit disorder, substance abuse, migraines, and irregular sexual maturation.
MAO inhibitors are one of the major classes of drug prescribed for the treatment of depression, although they are often last-line treatment due to risk of the drug's interaction with diet or other drugs. Excessive levels epinephrine, norepinephrine or dopamine may lead to a hypertensive crisis, and excessive levels of serotonin may lead to serotonin syndrome.
MAO-A inhibitors act as antidepressant and antianxiety agents, whereas MAO-B inhibitors are used to treat Alzheimer’s and Parkinson’s diseases.

Clonidine in ADHD
In the US, the FDA has licensed clonidine for use in children with ADHD.
Pediatric doses of clonidine are calculated based on the child's body weight. Clonidine dosage for ADHD in children is 5 micrograms per kilogram of body weight per day orally in four divided doses. Children who require a daily dosage of 0.2 mg usually can use the 0.3 mg trans-dermal patch. If ADHD is associated with sleep disturbances, low to moderate doses of clonidine can be taken at bedtime.

Clonidine in Autism
Not surprisingly, since clonidine is effective in ADHD, it also shows promise in autism. 

Other ADHD drugs, like Ritalin, have problematic side effects.  The US Center for Disease Control reported in 2012 that an estimated 6.4 million children ages 4 to 17 had been diagnosed with ADHD at some point, a 53 percent increase over the past decade. Approximately two-thirds of those currently diagnosed have been prescribed drugs such as Ritalin or Adderall. Those drugs can help patients with both mild and severe symptoms, but they can also cause addiction, anxiety and psychosis.  In the UK, it is suggested that about 3% of children may have ADHD.  Drug use is far lower than in the US, but 657,000 prescriptions were written by doctors for drugs like Ritalin in 2012.
There have been studies of clonidine in autism; here a fairly recent one:-
Perhaps even more interesting is a lively debate among parents who have tried it:-
It does seem to work, but nobody seems to be following it up.


Clonidine Stimulation Test
Regular readers will know my interest in TRH and GH.  At least there is no doubt about Clonidine’s effect on GH (growth hormone).  If you want to test pituitary function to see how well GH is being produced, the standard test is the:-
For those interested in GH, if you were to take Clonidine, smoke a cigarette and then have your GH measured, the Endocrinologist would have a surprise.

“These findings suggest that in man nicotinic cholinergic and adrenergic mechanisms might interact in the stimulation of GH secretion.”
 



Interestingly, one of the milder side effects of the ADHD drug Ritalin is growth retardation. According to Professor Tim Kendal, who created the national guidelines in the UK for treating ADHD: - “In children, without doubt, if you take Ritalin for a year, it's likely to reduce your growth by about three-quarters of an inch.


Conclusion
Clonidine looks like another old drug that has been stumbled upon by somebody doing some off label experimentation.  It does seem to have good results in ADHD and Autism.  The good thing is that it is FDA approved and is available in both oral and time release transdermal forms.
I do not think anybody really understands how it works in ADHD or other psychiatric disorders; undoubtedly, there is another, as yet unidentified, mode of action.
 
For those who want more info:- 




Note ulcerative colitis, ADD and even growth delay.

 
 
 

 

Monday 11 November 2013

Creatine, the Sub-types of Autism is Affects, and the Missing $26 million



Poly Genetic Theory of Autism

Autism appears to be the result of the expression of multiple abnormal genes acting in concert, likely initiated by some external factor(s).  This would explain why there are so many variants of autism and why there can seem to be autistic-like traits in close relatives.
 

 

Gene-based Autism Research
Several candidate genes have been identified, such as those linked to fragile X syndrome, tuberous sclerosis etc.  Researchers then follow the science from the target gene to identify a possible therapy.  At this point the researchers then seem to lose their scientific logic; they then try and apply their new therapy to all kinds of autism, i.e. the ones without the “faulty gene”.

This really goes back to our current limited understanding of the brain, medicine is more art than science, and we should perhaps suspend logic and accept this trial and error approach as valid.  At least call it trial and error.

Creatine
Creatine is an organic acid produced naturally in the body.  It helps to supply energy to all cells in the body. This is achieved by increasing the formation of adenosine triphosphate (ATP).

Creatine is not an essential nutrient, as it is manufactured in the human body from L-arginine, glycine and L-methionine.
Its main use as a supplement/drug is among people wanting to develop their muscles, like athletes and bodybuilders.  Taking the standard dose of 5-10 mg has the same effect as eating a very high protein diet.  In people with muscle wasting diseases, Creatine is also used.  What I found interesting was the research showing an effect in depression.  There are marked similarities between conditions like depression and ASD.
We will return later in the post to another reason that Creatine may be relevant to autism; it appears to be something the research community did not notice.  Now back to those professional researchers:-
 
Creatine Deficiency
Science has identified three types of Creatine deficiency and all three lead to mental retardation and/or autism.  Two types are very rare, but are treatable; the third type is far more common, affecting about a million people worldwide, and is currently untreatable in humans.  In mice, this third type has been “cured”, but the money is not yet available to develop and test a human version of the therapy.
 
 
1.      AGAT 
AGAT (L-Arginine:glycine amidinotransferase) is an enzyme.  This enzyme is needed for the body to produce Creatine.  AGAT deficiency will cause Creatine deficiency  and lead to mental retardation and autism.
For those regularly following my blog, please note the following: It has been suggested that AGAT activity in tissues is regulated in a number of ways including induction by growth hormone (GH) and thyroxine (T4).

The actual genetic mutation associated with AGAT involves a tryptophan codon being converted to a stop codon at residue 149.
You may recall in my post on serotonin, we learnt about its precursor tryptophan and how it appears to be degraded in the autistic brain.


2.     GAMT
GAMT (Guanidinoacetate N-methyltransferase) is another enzyme required to produce Creatine.  As with AGAT deficiency, if you are deficient in GAMT, autism and mental retardation will follow.

Treatment
If diagnosed, defects of Creatine biosynthesis are treated with Creatine supplements and, in GAMT deficiency, with ornithine and dietary restriction of arginine through limitation of protein intake.
 
3.     X-linked Creatine deficiency
The final type of Creatine deficiency is much more common, but is much more difficult to treat.  The defect is the Creatine transporter that should allow the Creatine into brain cells, where it plays a critical role in the brain’s energy needs.  No matter how much Creatine you give to people with this disorder, they cannot use it, because their Creatine transporters (CRTs) are defective.

Fortunately, thanks to Dr Joseph Clark, Professor of Neurology at the University of Cincinnati, there is light at the end of the tunnel.  Dr Clark has been researching the Creatine metabolism for some years.  Very unusually, he has been sharing his experiences with us, via his blog.
To cut a long story short, the good doctor has figured out that by using an analog (a modified version) of Creatine called cyclocreatine he could normalize the function of mice with  X-linked Creatine deficiency.  All he now has to do, is to make it work in humans, fully test it and get it FDA approved.  The problem is there is no more money.  In his blog post he tells us that all he needs is:-
$26 million and three more years

Here is the official report from the University:- 
 
Peter’s thoughts on Creatine
I started looking at Creatine because it appears to stimulate IGF-1 (insulin-like growth factor 1).  This is not a fact well-known to endocrinologists, but it is very well known to athletes and body builders.  They take Creatine orally and it stimulates muscle growth.  Research has even measured the change in IGF-1 in muscle tissue resulting from Creatine supplementation.

In a recent post I pointed out that IGF-1 is itself being used in autism trials, as is a novel Australian analog of IGF-1 [1-3] called NNZ-2566.  The big advantage of NNZ-2566 is that it is taken orally.

The release of IGF-1 is stimulated by growth hormone GH.  Secretion of growth hormone (GH) in the pituitary is regulated by the hypothalamus, which release the peptides Growth hormone-releasing hormone (GHRH) and Growth hormone-inhibiting hormone (GHIH) into the blood surrounding the pituitary. GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion.
Stimulators of growth hormone (GH) secretion include:
  • peptide hormones
    • GHRH  through binding to the growth hormone-releasing hormone receptor
    • ghrelin through binding to growth hormone secretagogue receptors
  • sex hormones
    • increased androgen secretion during puberty (in males from testis and in females from adrenal cortex)
    • estrogen
  • clonidine and L-DOPA by stimulating GHRH release

·         α4β2 nicotinic agonists, including nicotine, which also act synergistically with clonidine 
      (Interestingly clonidine is a drug used for ADHD, or autism-lite, as I call it)

Factors that are known to cause variation in the levels of (GH) and IGF-1 in the circulation include: genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake. The later inclusion of xenobiotic intake as a factor influencing GH-IGF status highlights the fact that the GH-IGF axis is a potential target for certain endocrine disrupting chemicals. These are chemicals found in both household and industrial products that are known to interfere with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for development, behavior, fertility, and maintenance of normal cell metabolism. 
Based on my earlier primary research, I am pretty sure that in the sub-type of autism I am dealing with, there is a deficiency of either GH or TRH, in the brain.  As I result, I am interested in mention of these hormones.


 SHANK3 deficiency
(also known as 22q13 Deletion Syndrome or Phelan-McDermid Syndrome)

IGF-1 is being trialled at Mount Sinai Hospital in New York in autistic children with SHANK3 deficiency.  In true “art” rather than “science” approach, the plan is then to trial IGF-1 on children without SHANK3 deficiency.

Here is a good explanation.
If you live in the Big Apple:-

Where Can I Get Testing?


The Icahn School of Medicine at Mount Sinai offers genetic testing for Phelan-McDermid Syndrome/22q13 Deletion Syndrome and for SHANK3 mutations. A blood sample is needed to conduct the test. For more information about testing, visit The Seaver Autism Center, call (212) 241-0961  

It appears that SHANK3 deficiency accounts for about 1% of autism cases.
If, as is hoped, IGF-1 turns out to be a useful therapy in SHANK3 deficient children, it will be tried on all ASD kids.  If it works, then what was the relevance of SHANK3 in the first place?   It seems pretty odd to me.  I think most likely our current understanding of genetics is so basic, as to be flawed.

I am working via observation, rather than genetics; I know what circumstances produce near neurotypical behaviour, I just need to understand what is going on biologically.  This is how I ended up with TRH and/or GH.


Conclusion
Well if the Mount Sinai study is successful, as it probably will be, we should find Dr Clark in Cincinnati and give him $26 million.  Then we put creatine and cyclocreatine in a pill and give it to ALL people with ASD, since 99% will never get their sub-type diagnosed. 

Either the creatine, the cyclocreatine or the extra IGF-1 will do some good, depending on the sub-type – something for everyone. And no needles.