Tuesday, January 3, 2017

                         DYSKINESIA DOSE SUSCEPTIBILITY RANGE
                                                         BY Sam Moore

I have found that my dyskinesia has a susceptibility range.  The range starts at about 100 mgs of levodopa IR and continues at levels of levodopa higher than I have experienced.  The Figure below shows the range I have experienced.   The intensity of the dyskinesea, when it occurs is proportional to the highest level just before the elimination period starts.  At levels less than the susceptible range is a safe range. This range starts at a level where the tremors cease.



The information is patient sensitive and will not be the same for everyone.  Relating the information to blood concentration, one hundred mgs. is equivalent to approximately 18.2 mg/ml blood concentration.  For my body weight, about 5.5 liters of blood.

The blue/green line is for 150 milligrams taken three times a day.  While I was on that protocol I did not suffer with tremors or dyscinesea.  I attribute that to the level being most of the time above the upper limit of tremors. I believe this dose level is too low to be therapeutically beneficial.

The red line is for 200 mg. taken 4 times a day. This was the worst I have suffered with dykinesea, both in length and intensity.   I never want to go through that again.  The higher the peak just before the dyskinesea, the higher the intensity.

I have been looking at profiles of  Rytary.  I think I have it down pretty good.  I understand that a friend of mine is taking Rytary, Two 95 mg. tablets, 4 times a day.  I worked up a model of Rytary so I could plot a graph of the daily profile.  The result is the graph, shown below.
.
From my experience, I have found that you can have a condition where you get enough levodopa to eliminate the tremors, without having enough to  be therapeutic.  If I am correct, in the protocol that my friend is on,  I believe she is at this point.  I have taken into account that she is a small woman and would not require as large a dose as a man my size.  I believe in order to have a therapeutic effect you must have enough levodopa to make you susceptible to dyskinesea.  Fortunately, with the Rytary protocol, the level of medication remains at a high enough level to prevent triggering of dyskinesea. In the plots,  I have shown the profile for the 190 mg. tablet.

I am attaching my dose profile for a comparison to the Rytary profile.  I use a protocol of sinemet, because it is cheap, that makes me take my doses every two hours.  It ends up putting me in a dyskinsea sensitive range much of my dose period.  That combined with the large fluctuations of medication level causes me to put up with dyskinesea several times every day.   It is not possible to have 24 hour coverage .  You are limited to 12 to 14 hours.   I miss doses on my schedule, because,  I sometimes am out of range of hearing of my timer, I forget to set or activate the alarm, or I accidentally turn the sound of my alarm too low to hear.


I am impressed by the Rytary profile, because you can get 24 hour coverage and it is less susceptible to Dyskinesea than my current protocol.   Except for the cost, I think Rytary is the best solution yet for a sinemet protocol.

I believe that for ease in comparing results between patients, it makes more sense to look at the profiles in terms of mg/ml, rather than in mgs.  Mgs/ml takes into account the weight of the patient with there associated blood volume.  In order to support this recommendation I have attached a graph with two profiles. One is of  two 95  mg. tablets of Rytary taken 4 times a day by a 155 lb. patient.  he other graph is of two 95 mg. tablets of Rytary taken 4 times a day by a 110 lb. patient.

As can be seen in the graphs,  the dose has a much stronger effect on the smaller patient.   This technique will narrow the gap for comparing results.
I believe that for ease in comparing results between patients, it makes more sense to look at the profiles in terms of mg/ml, rather than in ml.  This takes into account the weight of the patient with the associated blood volume.  In order to support this recommendation I have attached a graph with two profiles. One is of  two 95  mg. tablets of Rytary taken 4 times a day by a 155 lb. patient.  The other graph is of two 95 mg. tablets of Rytary taken 4 times a day by a 110 lb. patient.



As can be seen in the graphs,  the dose has a much stronger effect on the smaller patient.   This technique will narrow the gap for comparing results.

I hope you have found this article beneficial.  If so, please "Like" it on Facebook,  or comment on my blog.  Support PD research on the Michael J. Fox foundation.  Support this blog  with donations to my account  s_durwood_m@msn.com on Paypal, or contact sdurwoodm@gmail.com to send comments.  Both positive and negative comments are welcome, although positive ones are preferred. I will try to respond.                                                    



                         

Friday, December 23, 2016

                              HOW DO YOU EVICT SQUATTERS?

This is a story about troubles with the Parkinson’s clan.  

I have a problem with squatters that have moved in and wont go away.  It started out innocently enough.  It would be a situation that was unpleasant but tolerable.  It began about six years ago when the patriarch of the family moved in.  The family name is Parkinson.

Soon other members of the family showed up.  There were Tremor,  Stiffness, Lethargy,  Insomnia and several others that moved in and out.

It soon became intolerable.   I started looking for someone to help me get rid of the unwanted visitors.  I selected a specialist with important letters before and after her name, only to be informed that she had no solution for my problem.  I then found another specialist, again with impressive credentials.  He started out trying several approaches.  Some of the approaches did no more than temporally move some of the family out but they always returned.  He tried one approach that involved the marriage of the patriarch to Levo.  At this point, the marriage produced an unplanned son that was named Dyskinesea.  Dyskinesea was too much for the specialist so he recommended another specialist that had narrowed his specialty to the Parkinson’s family.

The new specialist was sold on the marriage of the patriarch to Levo.  He tried marriage counselling to increase the bond between the two.  This worked to some extent; however, the relationship had lots of ups and downs.  Part of the problem with the marriage was Levo's  chronic gastric problem.  The solution to the problem was getting Carbi involved.   Carbi and Levo were twins of the Dopa family,  and had been separated by the marriage.

At this point in time the relationships were complicated by an across the country move.  I moved to live with my daughter and her family.  She fixed up a nice apartment for my wife and me in her home.   

A perfect opportunity to get away from the Parkinson’s clan.  Think again, they found a sucker and they intend to milk it dry.  So now I have to start again.  First find a new specialist.  My fourth specialist was there in name only.  I think he had retired early and forgot to tell anyone.  

So the patriarch followed with his clan and his wife, Levo,  and moved in on us again.

I was getting desperate at this stage, so I decided to foster a romance between Dyskinesea and a new entry, Mary Jane.   Mary Jane became an option because she was living in the state of California,  where we had moved.   This was a failure, so I continued my search for a new specialist.  Enter number five.

Like number four, number five had also entered premature retirement..  At this stage I gave up and decided I would have to go proactive.  I started by going to the internet and researching the various aspects of the Parkinson’s clan.  

I discovered that the Dopa family was extremely sensitive to the timing of their involvement.  I used a timer to time my attempts at involving Levo in the relationship. An immediate improvement resulted.  Then I found that a greater improvement occurred when I adjusted the intensity of my attempts.  By adjusting the intensity of the attempts along with the timing of the attempts, I could get an amplification of the effect.

Something was still missing.  I had no way of correlating the intensity and timing with the timing of the response from Levo.  Then I found that others had measured the push back response of Levo.  I could then predict the action of Levo by plotting the intensity of the attempt against timing of the attempts.  At first I manually plotted the chart using “Paint” and the laws of geometry.  This was slow and tedious, but it was an improvement in performance.  I then went to the computer and developed a spreadsheet algorythm to have the computer generate and plot the data for me.

I tried to interest my fifth specialist in my discovery, but he didn’t want to be bothered with any new ideas.  I found a sixth specialist.  Number six was a jackpot.  He was interested in my approach and encouraged me to continue developing the algorythm.

Number six decided that arbitration was in order, so he brought in two negotiators to try to bring some peace to the family.  He decided on Amanta and Rogeta, two intercessors who were able to smooth over some of the rough spots in the inter-family relationships.  Getting the arbitration process going had its own rough spots due to the high cost of the Rogeta half of the team.  Negotiating the contract price was difficult in itself.

That brings the story up to date.  I still have the clan on my back, but it is more predictable.  My next effort is to help others who have the same problem as I have.

If any reader of this story has any ideas about this subject, please contact Sam at sdurwoodm@gmail.com.       




                HOW DO YOU EVICT SQUATTERS?” EXPLAINED

The short story  “HOW DO YOU EVICT SQUATTERS?” was written to put some humor into the other wise hum drum life of PD patients.  For most patients the story would make sense; however, for the person unfamilier with the levodopa treatment of PD, some of the situations of the story might not be clear.  I will attempt to give some baqckground on the most prevalent treatment of the disease.

First PD is a progressive disease.  As of this date, it is incurable.  The best that can be done is minimize the symptoms of the disease.  It is believed that either a deficiency of Dopamine or a defect in the ability of the brain to utilize the Dopamine for firing the syenapsis.  The inability of the brain to utilize Dopamine, causes erratic firing of the synapses, resulting in erratic responses in the movement of the patient and slowness of movement with sometime freezing of motion.  This symptom of PD is called Tremors.  Years ago, it was discovered that the medication, levodopa minimizes the symptom, dyskinesea, as well as the other symptoms that tended to immobilize the patient.  

The problem this treatment has severe side effects of its own.  By adding carbidopa to the dose, the symptom nausea is minimized.  The medication, brand name Sinemet, provides a 1:4 ratio mixture of carbidopa and levodopa.  This is available in a generic version with a number of absorption characteristics, Imediate Release, Control Release, Extended Release, and combinations of the three such as Rytary.  

The biggest drawback to levodopa is its short half life. The half life is approximately 1.5 hours.  This means that 1/2 the levodopa is eliminated within 1.5 hours.  In addition, the levodopa is a precursor to Dopamine.  The levodopa does not cross the blood/brain cell barrier, resulting in the requirement of a massive amount of levodopa being  required to provide adequate dopamine.  Most of the levodopa is eliminated and never reaches the barrier.

Combinations of the available characteristics are used to extend the length of time a therapeutic dose stays in the blood stream.  I work with the total medication in the blood stream for my profiles,  A simple conversion multiplier will change the total medication level, in milligrams  to blood concentration, in milligrams/milliliter.  The only added information required is the weight of the patient.

A plot of blood content of levodopa vs time of day gives the “Profile” of the day’s medication protocol.  This is a valuable tool in fine tuning the protocol for optimum results.  Even with the Profile optimized, the protocol is limited in its effectivity.  

With the goal of supplementing the supply of dopamine another approach was desired.  A search for a supplement to dopamine resulted in some agonist candidates. Two such agonist were found, Amantadine and Rotegotine.  Amantadine has been used for several years to relieve the dyskinesea created by a drop in the levodopa level.  It is available in a generic form.  It has an absorption time of approximately 3 hours and an elimination half life of approximately 16 hours.  Since the medication half life is long. the medication blood level remains relatively high throughout the day. Unlike levodopa, the medication crosses the blood/brain barrier.  I assume that the Amantadine has a chemical change in crossing the barrier.  The resulting agonist supplements the dopamine.  A relatively large dose is required to force the medication across the barrier.  The original use for Amantadine was as a deterant to some kinds of pneumonia. 

On the other hand the Rotigotine, is only available as a brand name medication, Neupro Patch.  The manufacturer selected a derma patch as the delivery system. Without financial help, I cannot afford the medication.  The patch is changed every 24 hours.  In the 24 hour period It delivers 45% of the total medication in the patch.  I have been unable to profile the patch.  The modeling is complicated by the dual  and relatively short half life combined by the characteristics of the delivery system.  I believe the total blood stream level, after several days stabilization, is considerably less than the medication delivered in the 24 hours.  Due to the high cost of the medication, some patients have resorted to wearing the patch for 48 hours, thus halving the cost.  I would not recommend that action even though 65% of the medication remains in the patch after 24 hours.  My intuition tells me the variation of medication level would cause an increase in the susceptibility to dyskinesea.

“Mary Jane” refers to my experimenting with PD’s response to medical marijuana.  I know of one case where medical marijuana has extended the quality life span of a cancer patient by several years.      THC is the ingredient in cannabis  that is said to reduce the  symptoms of PD and Dyskinesea.    It didn’t work for me but that doesn’t say it won’t work for others.    Another successful case for cannabis was for alleviating the withdrawal symptoms  from  opioids.  The patient had used opioids for several years for pain relief. When his pain went away he was unable to withdraw from the opioids because of sleeplessness and other  severe symptoms. With the cannabis he was able to overcome the addiction. 

If you found this blog beneficial donate to PD research with The Michael J. Fox Foundation.  Send your Likes or Dislikes to Sam at sdurwoodm@gmail.com.  You can support this blog through donations through PayPal for sdurwoodm@gmail.com.                              

Monday, December 19, 2016

                                 19 DECEMBER 2016

                                     DYSKINESIA DOSE SUSCEPTABILITY RANGE
                                            BY SAMUEL D. MOORE

I have found that my dyskinesia has a suscepability range.  The range starts at about 100mgs  of levodopa IR and continues at higher levedopa levels as far as I have experienced.  The Figure below shows the range I have experienced.   The intensity of the dyskinesea, when it occurs, is proportional to the highest level just before the elimination period starts.  At levels less than the suscepable range is a safe range.  
This range starts at a level where the tremors cease.  


The information is patient sensitive and will not be the same for everyone.  Relating the information to blood concentration, one hundred mgs. Is equivalent to approximately 18.2 mg/ml blood concentration.  For my body weight, about 5.5 liters of blood.  
 

Saturday, December 10, 2016

ROTIGOTINE PATCH TREATMENT FOR PARKINSONS DISEASE

10 December, 2016

ROTIGOTINE PATCH TREATMENT FOR PARKINSONS DISEASE
By SAMUEL D. MOORE


Rotigotine is a dopamine agonist.  It is used as a dopamine supplement in the treatment of Parkinsons Disease symptoms.  Unlike levodopa, it is used as a substitute for the deficiency of dopamine which is believed to be a factor in the PD symptoms.  Levodopa is a precursor to dopamine that is converted to dopamine as it penetrates the brain cell barrier.

The delivery system for the Rotigotine is a derma patch (Neupro patch) which supplies a more consistent flow of medication than the system used for other medications.  This method is used to minimize the wide fluctuations in the delivery of the medication.  For instance levodopa is delivered in instant release or controlled release tablets.  The result is a profile of blood concentration with peaks and valleys that are thought to exaggerate dyskinesia.  The goal is to provide a smooth flow of fuel for firing the synapses.  

The rate of delivery of Rotigotine is determined by the total medication in the patch and the surface area of the patch in contact with the skin.  The 4 mg. Neupro patch, I am using, supplies 4 mg. of medication in 24 hours.  To achieve this, the patch starts off with 8.89 mg. of medication. At the end of 24 hours, the patch still contains 4.49 mgs. of Rotigotine.

I have seen on the internet that some patients, in an attempt to save money, change the patch every 48 hours instead of the prescribed 24 hours.  On the surface, this looks like a good way to save on resources.  However, because of the short elimination half life of the Rotigotine, very little of the 4.49 mgs. is effective. Instead, it passes through the system without adding a significant amount to the medications blood concentration.  

The blood concentration averages about 25% of the 4 mg. level. The peak concentration after stabilization occurs shortly after the patch is changed, then it tapers off during the 24 hours.

I started Rotigotine with doctor’s samples.  For several months, I received a months supply, for $10.00., using a coupon, not realizing that the cost was driving me into the donut hole”.  When I found out the cost of a month’s supply, I realized I could not afford it, so I dropped it.  Since then, I have received a free supply of the medication from the UCB Patient Assistance Program.

Tomorrow, 11 December, 2016,  is the first anniversary of this blog.  It has received 500 hits, 0 Likes, 0 Dislikes, 0 Criticisms.   It has been a disappointment, but I have learned a lot, mostly about what I had forgotten and what I thought I knew.   I also started with a lot of misconceptions.  I wish I had started this journey earlier.

Sunday, May 29, 2016

                TREATING PARKINSON'S WITH CARBODOPA/LEVODOPA,
                        THE MOST IMPORTANT VARIABLE, continued
                                     BY SAMUEL D. MOORE


I found a neurologist that specializes in motion disorders, including PD. My first visit
with him resulted in the addition of 100 mg. of Amantadine per day to my protocol.  
This medication acts as an agonist to smooth out the low spots in the levodopa profile, 
my interpretation. So I am now taking seven tablets of carbodopa/levodopa 25/100 mg., 
one Nue-Pro patch, 4 mg., and one tablet of Amantadine, 100 mg. per day. 

The profiles of the medication are shown in Figure 1. The jagged curve is the levodopa 
profile. The first dose is two tablets, the rest are taken one tablet at a time at two hour 
intervals. The Amantadine is taken one tablet with the first dose of levodopa. The 
dyskinesia is plotted on the lower portion of the graph in % of maximum tolerance. 
 Admittedly, a very subjective parameter. It is on a scale of 0 to 100. Comparing 
Figure 1 to 2, the dyskinesia was more frequent on Figure 1.







Monitoring the dyskinesia is tedious. So I have not done it frequently. The persistent 
occurrance of the symptom after the last dose of the day is obvious. I think it can be 
minimized by a change in timing or magnitude of the Amantadine dose.







I chose a morning dose of Amantadine to minimize the effect it may have on sleep. 
 Before increasing the dose of Amantadine, I think changing the time of day I take 
the medication would be more informative. As shown on the graphs, the Amantadine 
is quickly absorbed and then falls of with a long half life. By changing the time I take 
the dose, I shift the time of the peak concentration of the medication.






Figure 3 shows the effect of shifting the dose time by 10 hours. That would put the 
maximum concentration of Amantadine at the time of the persistant dyskinesia period.





Figure 4 shows the effect of increasing the Amantadine dose by one-half tablet and 
taking the extra one-half dose 10 hours after the first dose. Being able to visualize 
the medication level seems to be a valuable diagnostic tool.






Thursday, April 21, 2016

                                MORE ON TIMING BETWEEN DOSES
                       THE MOST IMPORTANT VARIABLE IN TREATING 
                          PARKINSON’S WITH CARBODOPA/LEVODOPA
                                         BY SAMUEL D. MOORE



I would like to offer my dose profile program for sale. However I am afraid too many
would try to use it to fine tune their dose protocol without the advice of their neurologist. 
It would be better to convince the qualified neurologist to use it as a tool in fine tuning
the individuals protocol to maximize the therapeutic effects and minimize the dyskinesia. 
So far I have come against a blank wall. I personally am not a doctor and do not know 
the important therapeutic levels of the medication.  All the profile plotter does is give 
you a feel as to what phase of the profile you are in for comparison with one’s symptoms.

The plotter is very precise but limited in accuracy due to the many variables in a humans 
own diet, health, and numerous other undefined variables.

It took me awhile with lots of trial and error to realize how simple the model could be. It 
ended up that I divided the day into 96, 15 minute periods.  Using a linear model I 
inputted the absorption of levodopa into the bloodstream.  The published absorption time 
is 1 hour.   As a result I had a model of the input to the bloodstream during the day.   To 
this I applied the half life elimination rate.  I then plotted the result using a sample every 
15 minutes.  The published half life of the levodopa is 1,5 hours.

In order to put as much flexibility into the program as possible, I allowed the user the 
flexibility of changing the absorption time in .5 hour increments.  The half life can also 
be modified.  I allowed for up to six doses per day.  Each dose can be a different value.. 
The time between doses can be input in 15 minute increments.  The time between doses 
can be different for each pair of doses.

The program requires a spreadsheet program such as Excel or WPS.  I have not tested it 
with Excel.

I have not been able to get an answer to the question of what is the real goal of getting 
me to the maximum dose I can tolerate. Would you get the same results by finding a 
comfortable level?  What is the most effective, the maximum peak dose, the maximum 
average dose. the total dose, or some other criteria?  What is a therapeutic level of 
levodopa?  

Monday, April 4, 2016

        TREATING PARKINSON'S WITH CARBODOPA/LEVODOPA,
                  THE MOST IMPORTANT VARIABLE  

The neurologists do not know the importance of timing between doses in the use of Sinemet to treat Parkinson's Disease (PD).  It turns out to be the easiest way to fine tune the treatment to the needs of the individual.   I have struggled with adjusting my dose for about two years.  I am now getting a handle on it.  
The Motor Disorder Specialist, I was seeing, two years ago, started me with the prescription of one-half  tablet of carbodopa/levodopa, 25/100, taken three times daily.  His instructions were “take at least one hour before a meal and approximately the same time every day.”
I did fine on this protocol , so he increased it to one tablet, then one and one-half tablets.  No problems.  When I went to two tablets, dyskinesia set in hard.  I tried to back off on my on.   Big mistake.  Dyskinesia got worse instead of better.  After an emergency room visit, one week in the hospital,  and a couple of weeks in rehab, I returned to the doctor.  I later determined that dyskinesia had messed with my diaphragm simulating a heart attack.   The doctor convinced me to go back to two tablets and maintain that for a while. I did and the dyskinesia became tolerable.  Still a problem but tolerable.  The goal of this doctor was to get me to two tablets four times daily.  
At this time I made a big move, Texas to California.  Then insurance changes, with associated doctor changes. By December, 2015, I was struggling with two tablets four times a day.  At this time I decided to look into the medications and the disease.  I started by searching the internet.  
I noticed the medication had definite parameters that could lead to predicting the amount of medication in the bloodstream during the treatment period.  With the tool of “Paint”, I manually traced out the expected bloodstream levodopa level.  I called this a “DOSE PROFILE”. Lots of trial and error.  It’s amazing how your skills deteriorate after 20+ years of retirement.
By graphing out my medication protocol, and relating the plot to my symptoms, I soon saw the importance of precisely timing the doses. I discovered that it is impossible for me to time my doses without a timer.
I found a dose timer at Walgreens.  It operates in 1 hr. increments.  When I started using it, I found my symptoms much more predictable. 
After doing a number of graphs with “Paint” I developed an algorithm that I put on a spreadsheet and let the computer do the grunt work.  It used straight line approximations instead of logarithmic lines. I then went one step further and developed a mathematical model for my spreadsheet which I believe is adequate for my purpose.
My last visit to the neurologist he added a 4mg Neu Pro patch to my protocol.  I tried to interest my neurologist in my ideas.  He walked out of the room while I was still talking.  I am looking for another doctor.
A few days after adding the patch I started having more Dyskinesia, insomnia, nausea, and heart palpitations.  I changed the timing of my doses and dropped one tablet.  Boy what a difference.  After a few days, I feel better than I have in years. 
Currently I am using a countdown timer on my android phone on a modified protocol.  The attached figure is the output from my plotter on a protocol that is working well for me.