NAC and Rotten Eggs – Where to draw the line?

One effective intervention in autism, particularly to reduce stereotypy, is N-acetylcysteine (NAC).  Here NAC is being used as an anti-oxidant in its own right and as a precursor to the body’s own main anti-oxidant, called GSH.  Classic autism is associated with oxidative stress and so NAC should be beneficial.

In much of Europe, NAC is seen primarily as a pharmaceutical, in North America, and much of the rest of the world, NAC is primarily just another supplement.

As a drug, it is mainly used as a so-called mucolytic agent, and as such is used as a cough medicine, because it breaks down mucus and liquefies it, making it easier to cough up.  It is frequently prescribed by doctors for children, but only in some parts of the world.

The problem with NAC, and all supplements, is quality control.  There is pressure to drive down prices and so quality will vary.  NAC is not particularly stable (it is labile) and so it tends to break down and release some foul smelling compounds.

For those who remember chemistry from school, the chemical formula is C₅H₉NO₃S and the following chemical structure:

The smell of rotten eggs is associated with H₂S, hydrogen sulphide/sulfide.  The ‘S’ in NAC is sulphur/sulfur and so when it breaks down or oxidizes you get a nasty smell.

The question is how much of a smell is normal and how much means your cheap NAC capsule has spoiled to the point of being worthless?

There is plenty of online discussion on this subject among regular users of NAC.  As usual, much is nonsense; some people are even saying that NAC has to stink and that it is a sign that it is good.

When it is freshly produced, there should be very little smell.  When you open the pharmaceutical NAC from its blister pack there is no smell whatsoever.

Cheap NAC

Since you need large amounts of NAC for treating autism, I found a brand of the cheap NAC capsules, but I always open the individual capsules and mix them in juice.  I never had any stinky bad egg smell until recently.  Now as soon as I open the jar, let alone the capsule, there is a potent smell.  Try a jar from a different batch, same smell.  More to the point, I have noticed small signs of stereotypy when Monty, aged 10 with ASD, goes for a swim.  He is swimming in the water and then starts wiggling his fingers and looking at them.

So I have decided to switch to the pharmaceutical NAC, which where we live is called Fluimucil and is made in Switzerland.  You buy it in the pharmacy over the counter, but without a prescription.  The cheap NAC does not say where it is made, or even have a use by date.  I suspect that different batches are made by totally different producers, whichever offers the lowest price.

The well-known expensive brand of NAC sold in the US is actually produced in Europe, if it turns out to be Swiss, we can probably guess who is making it for them.

It is clear that when the cheap NAC is very fresh, it works fine, but I want a product that functions as it should, 100% of the time.

I will see if the small re-emerging signs of stereotypy disappear with the Swiss NAC.

PANDAS, PANS, Penguins and Autism

Anyone with a serious interest in autism should also be aware of PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) and PANS (Pediatric Acute-onset Neuropsychiatric Syndrome).  These are two syndromes which have acute onset of symptoms very similar to some of those found in autism.  It is claimed to affect 1 in every 200 children in the US.

The good news is that a very thorough and dedicated doctor called Susan Swedo has worked logically through from starting to identify the syndrome, all the way through to treating it.  Good job Susan.

Though she insists that PANDAS and PANS are distinct from autism, one can only wonder how many other distinct, but yet to be identified, syndromes exist that also present with autism-like symptoms.

Thanks to the efforts of Dr Swedo and the US NIMH (National Institute of Mental Health), these two conditions have been remarkably well investigated, in a very short period of time.  It shows what medical science can achieve when the right people are in charge.  It is odd that such effective clinical attention has not been focused on autism itself.

Here is a very recent presentation given by Dr Swedo, which really covers all the important aspects of both PANS and PANDAS.  For those with a serious interest, have a look though this post and then watch the presentation, to get the most from it.

Dr Susan Swedo (click for IPad users)

Penguins and PANDAS

One of the reasons I was so impressed by how PANDAS has been addressed, as opposed to the much more common autism, is the before and after data.  For example, many people talk about regressive autism, but nobody quantifies from what, to what.  Some children went from a spoken vocabulary of 10 words to 2 words, while others went from 500 words to zero; there is a profound (and relevant) difference.

In the case of PANS and PANDAS we have the before and after artwork from the affected kids. As usual, a picture is worth a thousand words.

I have no great panda pictures, but Monty aged 10 with ASD, brought back his artwork from school last week and pride of place goes to his picture of two penguins.  We were all more than a little taken aback to see it.  Did he really draw this? Unassisted?  It looks much more like the work of his big brother.  Even his assistant was surprised and confirmed that this was the result of his work in the art room for a double lesson.  I never expected to be displaying Monty’s artwork to the world.

Later in this post you will see the before and after PANDAS artwork.

PANDAS and PANS

When I first came across a condition known as PANDAS or PANS, I did not take that much notice; with such a name I assumed it was nonsense.   Researchers should give a serious syndrome a serious name/acronym.

I imagine that with the ever widening of the diagnosis of autism, some people with PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) /PANS (Pediatric Acute-onset Neuropsychiatric Syndrome) have been misdiagnosed as autistic and vice versa.

When you look at the symptoms and apparent cause of PANDAS/PANS you may wonder how many other similar conditions exist within the myriad of conditions leading to autism.

The shocking regression in cognitive function (illustrated by children’s drawings further down the page) produced by this condition and the fact that it can be reversed, should really be carefully evaluated in comparison to regressive autism.

It would be appear that all of this is caused by an immune system gone “haywire”.  I wonder how many other immune dysfunctions leading to regression and odd behaviours will be identified in future decades.

The treatment for all these current, and future, conditions are likely to revolve around immunomodulatory therapy, ranging from very cheap steroids (prednisone) to the very expensive, like IVIG (Intravenous immunoglobulin)

If you have a case of regressive autism and the expert says it does not fit the definition of PANDAS/PANS, he might think the case is closed.  Perhaps it should not be.

I suggest that immune over-activation is involved in both groups of autism:-

Early onset autism

In these cases the immune activation is secondary; when it occurs the existing autism just gets much worse.  In some cases these flare-ups are evidently caused by food allergies/intolerance or pollen allergies.

Regressive Autism

I think that in mild cases, some autism may be solely an over-activation of the immune system, without any of the channelopathies and other dysfunctions common in classic autism.  I would put PANS/PANDAS is this category.  I suggest that many other cases of regressive autism could be traced back to allergies and food intolerance, which triggered an immune over-response.

It does seem that many regressions followed a viral infection, and of course, many people believe their regression was triggered by vaccines.  I expect in most cases the vaccine is just a scapegoat, but I very much doubt it is in every case.   

I do not expect there will be any research in this area, because the results would inevitably be misinterpreted by the public.  What a pity.

If we better understood what events could radically disrupt brain function, we might be able to better understand how to treat the resulting neuropsychiatric phenomena, known as regressive autism, PANDAS, PANS and other, yet to be invented, acronyms.

A serious condition with some serious followers

Many people’s knowledge of autism seems to come from sound bites from scientific luminaries like Oprah, Jenny McCarthy and even Donald Trump.  Somewhat remarkably, the PANS doctors are actually a very serious bunch, under the umbrella of the International OCD Foundation (and the NIMH).  This foundation is a serious organisation with a scientific advisory board loaded with people from top US Medical Schools.

Not only have they concisely explained the symptoms, but they have also found therapies; albeit, they do not really know why they work.

The US National Institute of Mental Health has great information.

There is also a very serious parent run organisation called PANDAS Network.

About PANDAS and PANS

In the early 1990s, 50 years after Kanner noticed autism, researchers in the US noticed what they thought was an odd acute-onset type of Obsessive Compulsive Disorder (OCD).  At first it was thought that only streptococcal infections and Scarlet fever triggered this abrupt regression in the child’s behaviour and cognitive performance.  The first name they came up with was PANDAS, (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections); when reports came in that many other infections caused acute regression the name got changed to PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). 

From Research Subgroup to Clinical Syndrome: Modifyingthe PANDAS Criteria to Describe PANS (Pediatric Acute-onset NeuropsychiatricSyndrome)

Symptoms of PANS

It is pretty clear to me that some people diagnosed with regressive autism actually have PANS.  I have from two sources a list of symptoms:-

International OCD Foundation

• Acute sudden onset of OCD
• Challenges with eating, and at the extreme end, anorexia
• Sensory issues such as sensitivity to clothes, sound, and light
• Handwriting noticeably deteriorates
• Urinary frequency or bedwetting
• Small motor skills deteriorate - a craft project from yesterday is now impossible to complete (see images below)
• Tics
• Inattentive, distractible, unable to focus and has difficulties with memory
• Overnight onset of anxiety or panic attacks over things that were no big deal a few days ago, such as thunderstorms or bugs
• Suddenly unable to separate from their caregiver, or to sleep alone
• Screaming for hours on end
• Fear of germs and other more traditional-looking OCD symptoms

US National Institute of Mental Health

• Severe separation anxiety (e.g., child can't leave parent's side or needs to sleep on floor next to parent's bed, etc.)
• Generalized anxiety. which may progress to episodes of panic and a "terror-stricken look"
• Motoric hyperactivity, abnormal movements, and a sense of restlessness
• Sensory abnormalities, including hyper-sensitivity to light or sounds, distortions of visual perceptions, and occasionally, visual or auditory hallucinations
• Concentration difficulties, and loss of academic abilities, particularly in math and visual-spatial areas
• Increased urinary frequency and a new onset of bed-wetting
• Irritability (sometimes with aggression) and emotional liability. Abrupt onset of depression can also occur, with thoughts about suicide.
• Developmental regression, including temper tantrums, "baby talk" and handwriting deterioration (also related to motor symptoms)

In case you want to see what they mean by regression, look at these pictures drawn by a child with PANDAS before and after treatment.  Panel A is before and Panel B is after.   Source International OCD Foundation

  

Treatment

Compared to Autism, a very refreshing approach is taken to treating PANS.

The treatments include:-

·        Treatment with antibiotics to eradicate the infection, if it is still present.

·        Immune-based therapies such as

o   Plasmapheresis

o   intravenous immunoglobulin (IVIG)

o   corticosteroids (such as prednisone).

The good news about the immune therapies is that the treatment gains were maintained long-term, which is exactly what you would want to see. 

Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood

Implications for Autism

In spite of what your doctor might tell you, if your child has regressive autism, you would be well advised to check and re-check that he/she does not have PANS or a (yet to be identified) variant thereof. 

The immune-based therapies that ultimately are proved to be successful in PANS are highly likely to be helpful in treating the kind of autism in which the immune system remains in a state of over-activation.  Also the immune-therapies being trialled for autism, if successful, might very likely be helpful alternative therapies for PANS; the therapy I have in mind is TSO.

Classic early-onset autism, as researched in post-mortem studies at the Courchesne lab and elsewhere, is associated with physical brain abnormalities, that should be irreversible.  It would seem that PANS is something entirely different and should be treatable and potentially fully recoverable.

For those of you unaware of Courchesne, here is a short video; he is quoted by many of the leading autism researchers, so I hope he has got things right.

Eric Couchesne &Karen Pierce from University of California at San Diego

Where does regressive autism fit in?  I really doubt that all those people with regressive autism have the physical brain abnormalities of classic autism.  Research has shown that regressive autism has even higher bio-markers of neuroinflammation than classic autism.  Perhaps regressive autism is neuroinflammation, without physical brain abnormalities?

Just as PANS is a mini-spectrum of conditions, pathologically distinct from early onset autism, I suspect that regressive autism is equally pathologically distinct from early onset autism.

Why does it matter?  Well if you want to treat something, it helps to know what you are dealing with.

PANS looks like it has some clever people working on it.  Regressive autism, which may indeed be the most prevalent type, is in need of some similarly clever people.

Conclusion

If regressive autism is your area of interest, I would suggest you look very carefully at PANS/PANDAS and the therapies that have been shown to be effective.

If you have PANS/PANDAS, taking a look at the experimental immunomodulatory therapy used in autism might be very worthwhile, for example the TSO therapy from Coronado Bioscience.

We know that PANS/PANDAS is caused by an ongoing inappropriate immune response, but we do not know how this is mediated into the odd behaviours.  One possible mechanism would be via a weakening of the blood brain barrier (BBB).  

It has been shown that the similar mechanism controls the BBB and the gut immune barrier.   Clever research into Celiac Disease has resulted in the discovery of Zonulin, which is now known to be the only physiological modulator of both these barriers.  Using a type of laboratory test called ELISA, it is now possible to measure Zonulin levels.  If people diagnosed with PANS/PANDAS were shown to have low Zonulin levels, we could assume that the BBB was compromised; this would certainly advance understanding of the condition. It would of course point the way to new therapies.

Cognitive Enhancement, Classic Autism and School

The school year is coming to an end and now we get the results of assessment week, the end of year tests.

Personally I never liked exams, or rather revising for them, but for teachers, assessment is a big part of what they do.  I used to be asked at the start of the school year for a list of benchmarks to measure my son Monty’s progress during the year, since the usual benchmarks were seen not as applicable.  Then we would spend lots of time discussing the list.

Typical kids just follow the standard curriculum and get their standardized progress tests.  If you follow an ABA program, you are constantly measuring performance and you only progress when you master a skill, so it is like continuous assessment.

Monty, aged 10 with ASD, goes to a very small international school.  So there is no special needs teacher, no IEP (individual educational plan), just a nice friendly environment.  This works very well because it means you can build your own educational system, not restricted by any rigid rules.

From the age of about four years old till seven or eight, in effect, Monty’s curriculum was the ABBLS (Assessment of Basic Language and Learning Skills), which is a rather intimidating list of 544 skills from 25 skill areas including language, social interaction, self-help, academic and motor skills that most typically developing children acquire prior to entering kindergarten.  These are very basic skills, that we never had to teach to Ted, Monty’s big brother, but without these skills you really cannot do much. They are the basic skills on which everything else is built.  It includes things like toilet training, stacking coloured blocks in order and, at the intellectual end, involves ultra-basic speech, being about to count and being able to read.

When your child has just a handful of these 544 skills, it appears that you have a mountain to climb; indeed you do.

Fortunately for us, Monty’s then Assistant and best pal, Irena, took on much of this daunting task.  He did become verbal, he did learn to read, he learned how to write and yes, finally, got to grips with numeracy.  (All without any help from drugs)  

This all occurred in parallel with going to "school".  The learning all occurred at home, school was just for practice.

Back then, the end of year report did not really have much importance.

At some point you do hope that school will actually be a place for learning.

It does appear that in many cases of “inclusion”, school is little more than daycare.  Some special schools are brilliant, but even if you live near one, they tend to be hugely expensive and access is highly restricted.

My observation of the limited number of people with autism I am familiar with, is that they tend not to get on with each other; they actually like to be around nice friendly neurotypical kids.  Until you get to secondary school, many kids are nice to special needs kids.  After that, most really are not nice at all, and any idea of going to school for “socialization” becomes nonsense, because the “normal” kids openly seem to ignore, provoke and even hate the kids with HFA/Asperger’s.  Sad, but true.

What is Normal for Kids with Classic Autism?

Most kids with classic autism end up in a special school, or a special needs unit attached to a mainstream school.

One of our former 1:1 assistants was a trainee at the local special school and later became a teacher at another one.  We discussed what went on there and I did visit a few the school a few times.  It was much better than I expected, but was more about keeping the kids calm and under control, than academic advancement.  There were 6 kids per member of staff and the kids had very mixed ability, they were just grouped by age.

I took a look at Treehouse, the leading autism school in London, to see what is in their curriculum.

In the US there are many such schools.  In Europe, Treehouse is quite well known, because it seems to be unique.  One of our former ABA consultants from the US used to work at Treehouse and another former one is on the Board of Governors.  Our current ABA consultant was doing her PhD in Behavioral Science in the US, when the founders of Treehouse visited the leading US autism schools for inspiration many years ago.  A small world indeed.

In fact the Treehouse curriculum bears little resemblance to what goes on in mainstream schools.

I really do not understand what kids with classic autism can achieve in big mainstream schools, even with an assistant.  I just discussed this with Monty’s teacher, how can you “include” a child who has no understanding of what you are teaching the other kids?

Two year ago I agreed with our school to hold Monty back by two years, to be at his academic level, so he is two years older than most of his classmates.  There is no rush to get to secondary/high school.

The question I have had for a long time is whether Monty will be able to learn at school.  To date he has had thousands of hours of 1:1 learning at home, following his home program, which now combines ABA-based learning of things like social skills, conversation etc., with academic work like numeracy and verbal comprehension.

School for Learning?

My plan, when I realized that drug interventions do really cognitively improve autism, was to retain my model of school in the morning and 1:1 learning at home in the afternoon and aim for a time when school could genuinely be for learning.

The good news is that we really do seem to have reached that point.

I had the end of year meeting with Monty’s class teacher and it was almost as if we were discussing a regular kid.  For a start, we were discussing results from standard tests for science, maths and English provided by Cambridge University for international schools following their primary curriculum, so much less scope for the usual “sympathy grading”.

Lots of kids do get extra time in tests, for example if they have dyslexia.  Why not for autism?    The Asperger’s boy in Monty’s brother’s class gets an easier English test and extra time.

In Monty’s case, I did not want extra time; anyway he does not need it.  If he does not understand what to do, extra time is no help.  The question was whether his assistant should give him any “hints” as to what the questions mean, when she knows he really does know the answer. (e.g. when asked verbally by the teacher, so not in writing,  "what is the next factor of 5, after 30")

We had this debate and we agreed; no help of any kind.  That way at least the test tells us something useful.  If the test is based on prompting/help, how big was the prompt?  Better to see the real result and then we can do the “oh, but he really can do that”.

So this year was the first time we have the same tests as the other kids and definitely no help.  This is the result:-

Speaking and Listening        C+

Reading                                 B+

Writing                                   B+

Mathematics                          C+

Science                                  A-

ICT                                         A+

Music                                      A

Art                                           A

Well the results show Monty ended Year 3 ahead of anyone’s expectations, including the teacher.

I think the art teacher was probably being over generous, which is what tends to happen (sympathy grading).  ICT (Information and Communication Technology) is pretty basic at this level, but Monty can do it all.  When it comes to music, Monty is in his element; he can read music, plays his piano and has started to sing.

So the grades seem to be genuine, and he was not at the bottom of the class in any subject. That might not be a common educational benchmark, but I think it is a pretty good one to see if “inclusion” is really working.

As I said to his present teacher, only two years ago he was hitting his then class teacher, assistant and even, on rare occasions, his classmates.  Back then there was very little learning going on at school and not much social interaction either.

Cognitive Enhancement

Along with greatly improved social skills, simple conversation with peers, and even some sporting ability, has come cognitive enhancement.  He still is not “normal”, but it is a remarkable transition nonetheless.

How far he can get following the mainstream curriculum is an open question, but it is far further than anyone could have dreamed of, until he started his drug therapy.

I continue to be amazed, but the gains are almost entirely reversed if he stops taking his drugs.

PAK1 Therapy for Autism – All packed and ready to go!

Following up on recent posts about PAK1, whose presence is required for 70% of cancers to grow and MIT have implicated in several types of autism, I have collected all the data I can find to make trials of PAK1 inhibition in autism.

  

I contacted the leading Japanese researcher who has developed PAK1 therapies for various kinds of tumor, mainly found in neurofibromatosis, but also brain tumors and even epilepsy.  He suggested the dosage of the CAPE-rich propolis from New Zealand and also suggested another drug called Fingolimod/Gilenya.  

This drug is an immunomodulating drug, approved for treating multiple sclerosis, but it is also a PAK1 inhibitor.  It appears to cross the blood brain barrier.  The downside it that Gilenya is hugely expensive, costing around $50,000 a year.

  

While Tonegawa's group at MIT continue to develop their new PAK1 inhibitors, I am concerned that they will end up with a drug costing as much as Gilenya, which will put it out of reach of most people, even if it was effective.

So that brings me back to the trials I propose.

Trial 1   -  BIO 30 Propolis

This is a natural product and as such will appeal to many of this blogs readers.  It needs no prescription from your doctor.  You can buy it over the internet from numerous pharmacies in New Zealand.

The dosage proposed for autism by the Japanese Researcher is 1-2 ml per 10 kg of body weight.

It appears that about 1% of people have an allergy to bee products.  If you are in the 99%, it is reported that even very much larger doses of BIO 30 have no side effects.

Trial 2   -  Ivermectin/Stromectol

This is the cheap drug that is used to treat parasites, but turns out to be a PAK1 inhibitor.  It was also recently shown to kill leukemia cells.

Here I will draw on the autism worm-dosage used by Dr Wu, who prescribes Ivermectin in the belief that the autistic kids’ behaviours are driven by worms.

Dr Yu is combining Ivermectin with other anti-parasite drugs.  I am assuming he “got it right for the wrong reason”, in other words the worms are not the issue, PAK1 is the issue.

Below is the dosage Dr Yu suggests in his autism presentation and one case report where there was a before and after evaluation.  Here the ATEC was used, which is a scale designed by Bernard Rimland and Stephen M.Edelson of the Autism Research Institute (the DAN people).

  

From what I could find, a single dose of Ivermectin (Stromectol) should kill the parasites.  Pets are given the same drug on a regular basis, some preventatively.

In low doses it appears to be very safe, but not in high doses.

Strongyloidiasis is a human parasitic disease caused by the nematode (roundworm).  On the site RXLIST.com the dosage for Strongyloidiasis is:-

The above is for a single dose therapy.  Dr Wu’s worms are either much more resilient, or his much higher and multiple dose therapy is actually working for entirely different reasons.

Trial 3   -   Fingolimod/Gilenya

Given the huge cost of Gilenya, I cannot imagine anybody trying it for autism.  Perhaps Novartis would like to donate some?

We did cover immunomodulatory therapy in earlier posts and it was Dr Chez who likes to write about this subject, in relation to autism.  He has published several trials and a good book.

Perhaps he should do the Gilenya trial?

The Blood Brain Barrier

I did ask the Japanese researcher if CAPE, the anti-PAK1 ingredient of the New Zealand propolis can cross the blood brain barrier, since it is claimed that Ivermectin does not.  He says that BIO30 and Fingolimod/Gilenya cross the BBB.

This brings me to a slight diversion.

Why inflammation leads to a leaky blood-brain barrier: MicroRNA-155

In this research the aim was to confirm the mechanism behind why inflammation causes the blood brain barrier (BBB) to leak.  It has been suggested that the leaky BBB is a key part of autism.  The less leaky it is the better for autism.  Since pro-inflammatory agents like histamine and IL-6 really do make autism worse, it is highly relevant that the research shows that pro-inflammatory agents cause the BBB to let through more of the substances that it is supposed to keep out.

Perhaps the ever-present pro-inflammatory cytokines found in autism, mean that the BBB is always partially compromised.  A drug like Ivermectin might therefore pass more freely across the BBB, than would be expected in other people.

So Ivermectin might remain a cheap alternative to Gilenya.  Dr Yu’s case studies perhaps warrant some more serious attention.

Will it work?

There are good reasons why PAK1 inhibition should have a positive effect.  It is definitely not quack science, it is the serious MIT kind.

In treating Neurofibromatosis NF-1 tumors, it does seem to be more effective at stopping new tumors, rather than shrinking existing ones.   This perhaps should not be surprising, since PAK1 is needed for a tumor to grow and may not be needed for it to live.  At much higher doses, it is reported that existing tumors shrink. So with autism, maybe PAK1 is needed early on, before birth; blocking PAK1 in a 10 year old may be pointless.

The only way to find out for sure if it works in your type of autism is to try it.

If it does not work for Monty, aged 10 with ASD, we cannot say it will not work in somebody’s two year old with a different type of autism.

Also, in Monty, the PAK1 effect might already be being mitigated by his existing drugs.

It would be helpful if there was a clinical trial, but there is not.

Conclusion

Trial 1 is easy to do at home, and if you do it for a month, you would need two bottles of propolis, costing $50 including shipping from New Zealand.

Since the Nobel Laureate from MIT tells us that autism requires PAK1 and that, in mouse models of autism, PAK1 inhibitors are effective treatments, it seems odd nobody has tried it.  In PAK1-driven Neurofibromatosis, there are now many people claiming BIO30 to be effective.  In this condition you can measure/count the tumors, so I guess they should know if it works.

The MIT-inspired drugs, like Tonegawa’s FRAX486 will not be available for many years, and who knows how much they will cost.

In the case of Ivermectin, somebody really should look at the toxicology data and see how safe regular usage would be in humans.  The Leukemia researchers proposed this drug be actively developed, but nothing seems to have happened.  Just for a few days, Trial 2 would not seem to be too risky.

We agree to leave trial 3 to Dr Chez, in Sacramento.