Masitinib

Masitinib is a tyrosine kinase inhibitor (TKI) being developed by AB Science to treat symptoms of amyotrophic lateral sclerosis (ALS). The treatment is advancing in clinical trials as a possible therapeutic for numerous disorders, from cancer and inflammatory diseases to those of the central nervous system, such as ALS. Trial results expected in 2021

Masitinib

Ibudilast

In late 2018, it was found that a drug called Ibudilast used for Asthma treatment in Japan showed very positive results for ALS patients. MGH Boston started phase 3 trial with selected patients in December 2018 and will publish results sometime later this year 2019. In the mean time FDA has already approved this drug on a fast track approval on April 17, 2019. Although there is no real cure for ALS, So far FDA had approved 3 drugs, labelled as treatment for ALS, namely Riluzole(Rilutek), Radicut(Edaravone) and Ibudilast(Ketas). If you want to get this medicine, it is available in Japan,  and can also be ordered through the web.  One such location a friend of mine was able to order is https://www.mimaki-family-japan.com/item/list?keyword_pc=ibudilast&x=0&y=0   In India to order you will need a Credit Card that allows international purchases.  In India, it is preferable to have a import license which is  Form 12A which can be obtained from the site https://cdscoonline.gov.in/CDSCO/homepage To obtain this license you will need to attach a doctor’s prescription. Indicate while ordering the import license that it is for personal use and this life saving medication is not available in India       https://alsnewstoday.com/2018/07/11/phase-2-als-trial-shows-ibudilast-rilutek-improves-function/

Telbivudine

In December 2018, it was found that a drug called Telbivudine used for Hepatitis B treatment in Canada showed very positive results for ALS patients.  University of Alberta is starting a phase 3 trial with selected patients https://www.sciencedaily.com/releases/2018/12/181218123120.htm

CuATSM

  New ALS drug slows disease progression in groundbreaking clinical trial Work on the drug, known as CuATSM, began over 15 years ago. At first it was thought that an excess of copper in the brain was the problem, but the researchers soon realized the opposite may be true. “The initial focus of our work was on Alzheimer’s disease where it was thought that copper drove the formation of amyloid plaques,” Professor Kevin Barnham, co-developer of CuATSM said back in 2017. “We reasoned if you could just remove this copper you could eliminate plaques, and you’d have the solution. Then we thought, perhaps it’s the other way around? Maybe cells are expelling the copper and so we’ve actually got a situation of copper deficiency. So, what happens if you deliver the copper back?” And that’s just what the new drug does. CuATSM is a compound that can penetrate the blood-brain barrier and deliver copper to the cells that need it. After tests in vitro and in animal models showed promise, a Phase 1 human clinical trial began in late 2016 to find the right dosage. I have been following this research for a while and tried contacting professor Kevin Barnham and Peter Crouch in Melbourne, Australia. The main genes that seem to cause ALS that they are investigating are SOD1, TDP-43, FUA and C9Orf72. Although there is tremendous hope for success for this drug, Unfortunately, they indicated that the drug will not be available for public for at least 3 to 4 years. Professor Kevin Barnham (Florey) and Associate Professor Peter Crouch (The University of Melbourne) take us behind the scenes of the recent news about the clinical trial of CuATSM (Cugtsm)for motor neuron disease https://www.youtube.com/watch?v=Ezj5iJCU5K4  

TEFERSEN from BIOGEN

https://www.pmlive.com/pharma_news/biogens_tofersen_shows_promise_in_slowing_down_als_1286593 Tofersen is being developed for ALS patients who carry the SOD1 mutation, which accounts for just 2% of ALS cases, but nevertheless plays an important part in the drug’s mechanism. During the phase 1/2 study, those dosed with tofersen over a three-month period resulted in a statistically significant reduction of SOD1 protein levels in the cerebrospinal fluid and a numerical trend towards slowing of clinical decline as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R).   https://newatlas.com/als-mnd-drug-clinical-trial-success/58026/?amp=true  

Ropinirole Hydrochloride

TeT

Japan university’s clinical tests to use Parkinson’s drug for ALS

Ibudilast

In late 2018, it was found that a drug called Ibudilast used for Asthma treatment in Japan showed very positive results for ALS patients. MGH Boston started phase 3 trial with selected patients in December 2018 and will publish results sometime later this year 2019. In the mean time FDA has already approved this drug on a fast track approval on April 17, 2019. Although there is no real cure for ALS, So far FDA had approved 3 drugs, labelled as treatment for ALS, namely Riluzole(Rilutek), Radicut(Edaravone) and Ibudilast(Ketas).

If you want to get this medicine, it is available in Japan,  and can also be ordered through the web.  One such location a friend of mine was able to order is

https://www.mimaki-family-japan.com/item/list?keyword_pc=ibudilast&x=0&y=0

 

In India to order you will need a Credit Card that allows international purchases.  In India, it is preferable to have a import license which is  Form 12A which can be obtained from the site

https://cdscoonline.gov.in/CDSCO/homepage

To obtain this license you will need to attach a doctor’s prescription. Indicate while ordering the import license that it is for personal use and this life saving medication is not available in India

 

 

 

Rilutek

This medication is used to treat a certain type of nerve disease called amyotrophic lateral sclerosis (ALS, also commonly called Lou Gehrig’s disease). Riluzole helps to slow down the worsening of this disease and prolong survival. However, it is not a cure for ALS, and it does not reverse nerve damage or muscle weakness. Riluzole is thought to work by protecting the nerves in the brain and spinal cord from too much of a natural substance called glutamate that may be part of the cause of nerve damage.

Radicut IVY Treatment

Radicava or Radicut (Ederavone) is an FDA approved treatment option for ALS.

Edaravone is available in india. It was promoted as a neuroprotective agent for patients with acute ischemic stroke. Several generics are available. Edaravone (radicut) is also marketed in India by Edinburgh Pharmaceuticals and Sun Pharma by the brand name Arone.

The medication is Aravon and two of these bottles are mixed with 1 bottle of the NS solution for the I.V. per day. (20 vials per month). Aravon is made by Sun Pharma in India.
Edaravone cost is approximately Rs. 450 per vial

ALS Associations

There are few associations that can provide additional support:

www.alsworldwide.org

www.alsuntangled.com/

www.alsa.org/

 

Elysium

This supplement has been suggested for ALS patients to take 8 capsules per day in the morning

There are similar anti-oxidant supplements available in India. Vitamin C and Zinc are also recommended

COQ10 in liquid form are more concentrated dosage for nutrition. COQ10 comes in tablet form also.

These two oils are supposed to be good for any nerve related illness and one can add this directly to the cooked food before eating.

EnsurePlus  (15 scoops per day –  5 meals with 3 scoops each)

Threptin (6 biscuits per day in two meals)

 

 

Positive Attitude

One most important thing to do while dealing with ALS/MND is to work towards keeping a positive attitude, which is hard to do for a person with this illness.  Daily Meditation and Yoga are extremely good. These two books are a good read.

Tobii EyeTracker 4C with Optikey open source software

If you have a LAPTOP, the most cost effective device that one can use for communication for ALS/MND is a Tobii Eye Tracker 4C device ($169) with OptiKey open source software

Vikram, one of  the member of our MND group has created visual slides one can use

 

ALS/MND is a very complex illness and will need Multi disciplinary Care, namely,

Neurologist
Pulmonary Specialist
Speech Therapist
Nutritionist
Occupational and Physio Therapist
Psycho Therapist
Primary Physician to prescribe medicines
Nurse
Most importantly Family and Friends support

Hand and finger functions gets affected
Walking will get affected. slipping and falling is something to watch out. Please see a doctor who can provide orthopedic support to limbs.
Speech will get affected. Should contact a speech Therapist and find alternative ways of communication.
swallowing will get affected. Since Proper Nutrition is one of the most important factor in the management of ALS, if you find difficult to swallow, please get PEG feeding Tube surgery(direct to the stomach, not through the nose) as soon as possible. sooner is better that later in this case, and managing PEG feeding is not very difficult.
Respiration will get affected. will need BIPAP machine. If Respiration problem is severe, one may need Tracheotomy surgery.

Controlling Depression, Try to have a positive attitude towards life, meditation and positive thinking will help. Nuedexta is helpful with extreme mood swings, depression and excess saliva.

Orthopedics

The first thing to do is to see a doctor who can provide some orthopedic support to limbs.  The picture below is an example shoe support (made in USA).  You have to get a prescription from your doctor.  It is Carbon metal shoe insert and can be made from any orthopedic shop.

This is a plastic shoe insert made in India. This was made when we were in India-Gurgaon, Delhi

Given the complexity of this illness, simple copper supplements are unlikely to be useful to PALS with normal serum copper levels. We do not recommend using these.

ALSUntangled 43 copper

Patients and caregivers frequently asked about the effectiveness of alternative therapies and their use as treatments for MND.

In a recent study report that looked at the effects of ashwagandha, or Indian ginseng, in a SOD1 mouse model of MND, treatment of SOD1G93Amice with Withania somniferaextract improved motor performance and delayed disease progression.Withania somnifera reduced levels of misfolded SOD1and of phosphorylated NF-κB.

For around 3000 years Withania somnifera (WS), commonly known as ashwagandha or Indian ginseng, has been used in Ayurvedic and indigenous medicine around the world, and is thought to have powerful rejuvenating and life-prolonging qualities, and also have neuroprotective properties.This has been demonstrated in several models of neurodegenerative diseases including MND.

Further, the invention relates to the use of Mucuna pruriens seed powder or one or more Mucuna pruriens components, obtained from for the preparation of a pharmaceutical composition for preventing, alleviating or treating neurological diseases.

Nutrition

One of our friends in this group asked some information about diet while using PEG.  The same person indicated that he was giving 4 scoops of Ensure Plus per day.

After reading and doing a little bit of asking around, I feel that you are not giving enough nutrition.  If Ensure Plus is the only nutrition you are giving, according to the recommendation 4 scoops per day is way below the recommended 15 to 18 scoops per day.  According to the recommendation you are supposed to give 3 servings per day, each serving is around 50 grams (5 to 6 scoops) in 200 ml of water.  My wife, we give approximately 5 to 6 feeds per day and we give around 2 to 3 scoops per feed.  In addition, we mix the regular stuff that we eat such as boiled vegetables, dal, dalia, protein biscuits etc to the feed. Please check with your doctor and increase the intake as soon as possible.

Plant Extracts Used in Traditional Indian Medicine Eased Movement and Sleep Problems in Fly Model of ALS

https://alsnewstoday.com/2018/11/01/plant-extracts-used-in-traditional-indian-medicine-seen-to-ease-movement-sleep-problems-in-als-fly-model/

Regarding Stem Cells If I have to make few statements, here it is:

Although stems cells Therapy has provided excellent results for various illnesses such as Rheumatoid arthritis, Joint replacement, Osteoarthritis and sports injuries,

99.9% of all the institutions offering the so called Stem Cells Therapy for ALS are fake and dangerous.

Very few researchers are  legitimate, one of them being, Brainstorm-Cell Therapeutics conducting a study to see the

Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients being conducted at UC Irvine, Cedar Sinai Medical Center, LA, MGH Boston and Mayo Clinic Minnesota.

The study is expected to conclude in March 2020.

There are some other less dangerous stem cells therapy such as Stromal Vascular Fraction VF which is a newer form of stem cell therapy that is made up of stem cells harvested from adipose tissue (fat) found in our bodies.

My wife went through this type of stem cells therapy in Feb 2018 in New Jersey, it was safe, however, I am not sure if it helped her.

You are more microbe than human – if you count all the cells in your body, only 43% are human.
The rest is our microbiome and includes bacteria, viruses, fungi and single-celled archaea
The human genome – the full set of genetic instructions for a human being – is made up of 20,000 instructions called genes
But add all the genes in our microbiome together and the figure comes out at between two million and 20 million microbial genes
It is known as the second genome and is linked to diseases including allergy, obesity, inflammatory bowel disease, Parkinson’s, whether cancer drugs work and even depression and autism

The animals’ symptoms became much more severe after having a dose of antibiotics to kill their gut microbiome.
“We were very surprised,” said researcher Prof Eran Elinav, who could see the difference in the mice’s muscle and brain tissue.
The team honed in on the gut microbes and found 12 species that seemed to exist in much higher or lower numbers in the diseased mice.
By adding these bacteria, one species at a time, into mice with ALS the researchers showed some made the disease more severe.
One species Akkermansia muciniphila slowed the pace of the disease.
“But in no way are we implying we have stopped, cured or reversed the disease,” Prof Elinav told BBC News.
“The bacteria are in the gut, but disease is very far from the gut,” said Prof Elinav.
He added: “Our working hypothesis is this is done by secretion of small molecules that can penetrate into the bloodstream and then different organs.”
Researchers identified a chemical, called nicotinamide, that was being produced by Akkermansia muciniphila, which when injected into diseased mice also improved their condition.
It is thought the chemical is involved in minimising oxidative stress and preserving healthy neurone function for longer.
“It presents a very exciting prospect of understanding how our unique signature of microbes, and their function, affect processes not necessarily where the microbes live,” Prof Elinav said.
Does this happen in people too?
There is some early stage work in people.
Thirty-seven patients living with the disease had their blood, microbiome and in some cases spinal fluid compared with healthy people with whom they were living.
Again, differences were found in gut microbes and levels of nicotinamide in the body.
However, this is the limit of the human research and further trials are planned.
“We cannot overinterpret these findings,” Prof Elinav said.
“We cannot even think these findings are a new cure or treatment that people can do at home.”
Will this help patients?
The hope is further research will identify a drug that that can change the pace of the disease and buy people more time.
The Weizmann team is not anticipating a way of preventing or curing motor neurone disease.
Prof Elinav said: “This is a cureless, devastating disease.
“Doing something to slow down ALS is a very important step in a disease we have almost nothing we can do about.”
What do the experts think?
“This adds to an emerging, but still fuzzy, picture of a different metabolism that seems to occur in people with ALS,” Dr Brian Dickie, the Motor Neurone Disease Association’s director of research development said.
He added: “Diet and exercise are also being studied as potential factors associated with the disease.”

RCH4 is another compound that seems to reduce the progression of ALS. In fact in some publication, it indicates to be better than Rilutek(Riluzole) and Radicava(ederavone) in controlling the progression of ALS (MND).

The problem I see with this drug is that getting access may be a problem. It is being provided by a charity organization, and the site purports to represent a “group of retired scientists and doctors” in Europe who “discovered a previously unknown protein … which promotes ALS” and “designed a drug which safely stops production of the problem protein”. Also since they did not have proper funding, the drug has not gone for the FDA approval phase unlike Rilutek and Ederavone.

The normal level of Co2 is around 23 – 29

When breathing is impaired, your lungs can’t easily move oxygen into your blood and remove carbon dioxide from your blood (gas exchange). This can cause a low oxygen level or high carbon dioxide level, or both, in your blood.

High levels of carbon dioxide may cause drowsiness and — at the most extreme levels — unconsciousness, coma, and possibly death.

some of the symptom of high co2 are:

dizziness.

drowsiness.

excessive fatigue.

headaches.

feeling disoriented.

flushing of the skin.

shortness of breath.

Other related parameter to check are the Potassium level (normal level is 3.5-5.0)and the PH level. High Co2 with high pH (more than 7.45) requires medical attention.

CPAP /BIPAP machine and giving extra oxygen may help temporarily, However, CPAP/BIPAP can’t remove the carbon dioxide that builds up in the blood of people with chronic pulmonary diseases. you may need hospitalization.

If you are the primary care giver for your mother, and if she is on BIPAP, please try to take charge of few things. This is very important that you learn these and should not depend on somebody else.

Learn how to use a oximeter to check her oxygen and pulse. Please ask your doctor or nurse to teach you. A simple oximeter looks like this:
The oxygen value should be in the range 91 to 99. If it goes below 90 and remains below 90, you need to take immediate action which will vary based on the situation.
The normal pulse for adult should be between 60 and 100 and may fluctuate outside this range and if it does and remains high or low will need immediate action and will vary based on situation.

 

Learn to operate and set the BIPAP machine. Request your doctor/technician to teach you. Most of the BIPAP machine settings are quite straight forward
There are these 5 values that are important, namely, Mode, IPAP Min, IPAP Max, EPAP and Tidal Volume( A rough estimate of TV is 7* your weight in KG). Your doctor/Technician should visit your mother and help you set these values. For example the value used by my wife is below:
The BIPAP machine I am using is this:

 

 

The Example values will look like this and will vary from person to person.

 

 

 

 

Regarding Humidifier, you have two choices.  Most of the BIPAP machines comes with Humidifier Attachment

See Below:

The other choice is to use a Room Humidifier. There are quite a lot of Room Humidifiers in the Market that one can buy.

In both cases please keep track of the Water Level and use filtered water.

For patients with Tracheotomy, there is a third option of using HME Filter (Heat and Moisture Exchange Filter)

Information provided by S. Ramachandran

One of the most common problems that affects people with motor neuron diseases is called dependent edema. This is swelling of the hands and feet which gradually extends upwards into the arms and legs.  This is caused because veins depend on muscle movement to return blood and fluid to the heart. Without the muscle movement, fluid pools in the veins which become overloaded.   The fluid then starts to seep out of the veins into the surrounding tissue

Treatment

The swelling that follows cannot be reduced by diuretic medications (“water pills”). Elevating the legs or arms to a level higher than the heart is most helpful. This can be accomplished with positioning in a power wheelchair (tilt and recline and elevating leg rests), or in a bed by adjusting the leg position or placing pillows under the legs. Gentle massage with a lotion of preference can also help. Use the lotion to protect and moisturize the skin, which can be fragile if there is swelling. Massage from the toes or fingers always going upward toward the heart. This will help shift the excess fluid back into the veins and gravity will help the vein return the fluid to the heart in a more normal way. The massage motion is similar to the action of slowly working toothpaste from the bottom of the tube to the top.

Normally people associate swelling in legs with kidney function. I have seen my mother with calf swelling 15 years before ALS onset. This calf swelling couldn’t be explained by doctors as her other other health parameters including kidney function was perfect. Hence ALS can be in radar for explained calf swelling.

An arterial blood gas (ABG) test measures oxygen and carbon dioxide levels in your blood. It also measures your body’s acid-base (pH) level, which is normally balanced when you are healthy.
Arterial blood gas test results may show whether:
Your lungs are getting enough oxygen
Your lungs are removing enough carbon dioxide
Your kidneys are working properly

There are 4 important measuresment to look at

The Normal Values are:
Partial pressure of oxygen (PaO2): 75 to 100 millimeters of mercury (mm Hg)
Partial pressure of carbon dioxide (PaCO2): 35 to 45 mm Hg
Arterial blood pH: 7.35 to 7.45.
Oxygen saturation (SaO2): 94% to 100%

Here are two videos that is good for ALS patients

 

https://www.youtube.com/watch?v=bdELzsVmNLo

 

https://www.youtube.com/watch?v=k1Rywlj6TCU

By Satvinder

Sharing my understanding on some important aspects we learnt in this journey of understanding machine breathing.

1. Tidal volume should be 6-8 times of body weight in kg. E.g. 50 kg should be between 300-480. Start with lower side of range, so you can move forward to higher range when needed( with months/years time, alveoli regions available for gas exchange will get reduced). We started with 280 in 2010 and it was set around 400 in 2018.
2. Expiratory pressure or peep can be set to 6 comfortably.
3. Setting the breadth per min (BPM)could be tricky as there are many parameters which must be changed when you change this. Generally I feel 13-16 should be ideal. However, if your loved ones is comfortable with good oxygenation at lower or higher value- let that remains.
We started with 12, but during the time of machine received after servicing, this required change. This was around 16 in 2018.
4. Oxygenation in the body depends on volume of air exchange per min. E.g if you set BPM at 12 and tidal volume 300-300*12 equal to 3600 minute ventilation. While setting the same to 15 would lead to 4500 , a jump of 25% and you will see body oxygenation will automatically increase.(however, it should be rightly set according to total minute ventilation one should target according to weight and size of patient).
5. BPM of 15 means each breath made of 4 seconds. So we also need to see how we divide this to correct ratio of inspiratory and expiratory time. When you change anything, try to adjust inspiratory time to value which do not disturb this ratio. Sometimes tweaking here has a huge impact.
6. Now coming to using which machine – bipap, trilogy or any other machine. What we learnt is that *pressure* mode ventilation works best for ALS patients. So the target is to to achieve minimum minute ventilation atleast, so the mode should be set which has range of inspiratory pressure defined. E.g. *bipap avaps* . And good part is machines now have avaps rates (1-5) which is the rate by which machine try to increase or decrease the pressure, if set tidal volume is not achieved and that transition is smooth compared to volume modes
7. You need to keep monitoring for few minutes each breadth and it’s associated parameters displayed on screen to get idea if machine is actually doing what it designed for. I have seen two A40 machines, where this min pressure wasn’t increasing despite higher inspiratory pressure point was set, when tidal volume wasn’t achieved and machine kept on alarming LMV(low mins ventilation).
8. Our mother was too much against ABG test due to pain associated. So we hardly got that done.(only 4-5 times in first year). Main rule of thumb is – if patient is physiologically looking good + basic parameters fine in pulsoxymeter + ventilation in machine is looking good. No need for any investigations or ABG at all.

If you are in doubt about the BIBAP AVAPS setting the general guid line is to use these numbers for the following parameters:

Tidal Volume – 350 to 420
IPAP – 12 to 16
EPAP – 6
Breadth Per Min BPM – 15 to 16

The actual setting for the patient can be attained only after looking at the patients comfort level, speaking to doctors and some trial and error.

ALS patients do suffer Gas and Bloating if their stool motion is not controlled properly.
I have been giving 25 ml of Movicol Liquid with 50 ml of warm water every night for softening the stool
For immediate Gas and Bloating you may try
Gaia Herbs for Gas and Bloating or
Providac Capsules for Gas and Bloating
Also you may want to contact a doctor to check if there is any other issues.

Here is what I understand about Genetic Testing.

It’s important to understand that ALS is not just a single disease, but a collection of many different diseases that share the name — Amyotrophic Lateral Sclerosis(ALS) or Motor Neurone Disease(MND). At this time, there are more than 30 different genes that can fail or mis-fold that cause ALS to occur. Some people with ALS can’t speak but can eat. Others can speak but eating is difficult. Some can use their hands and arms but can’t walk. The myriad of symptom combinations is endless. There are more than 25 to 30 ALS pre-trial Drug Testing happening at various institutions that seem to target specific gene/genes and seem to show better results if patients genetic details are known.

In my wife’s case, gene sequence testing done showed negative for all the major genes that are known to cause ALS.  So back in December 2018, we were advised to continue with Ibudilast which seems to help general ALS patients. The Genetic Test was done through MGH Boston under the guidance of Dr Merit Cudkowicz.

My understanding of J-Tube versus a PEG is as follows:

If you already have stomach problems  such as acid reflex of food coming back and causing burning sensation or other stomach related problems, then the doctor may decide to go for J-Tube instead of PEG.  If you do not have such stomach problems, then PEG is much better and much easy to maintain.  PEG operation is much simpler and takes only 10 to 15 minutes.  It can be done using Pull method or Push Method.

https://www.youtube.com/watch?v=YjkZ6mQJ4JU

Actual video of a PEG operation

PEG cleaning Method

J tube operation is a more complicated.  J Tube is inserted into the opening of the small intestine and bypasses the stomach. Keeping the J-Tube in place inside the small intestine with clip is tricky and the clip may slip off causing problems.

https://www.youtube.com/watch?v=llQxfVFnLLA