Paper on achieving an optimised Levodopa Dosage

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Paper on achieving an optimised Levodopa Dosage

Achieving an Optimised Levodopa Dosage
Why do we need a Program?
Levodopa is by far the most significant drug which has been developed to combat the symptoms of Parkinson's Disease. While nothing is currently available which can halt or reverse the progress of PD, levodopa can help to mask the symptoms for several years, and so delay the point at which some of the major decisions of your life have to be made (When to retire, for instance). The problem is, that as the cells in the Substantia Nigra die, it becomes more and more difficult to provide just the right flow of levodopa to make up for the missing naturally-produced Dopamine. The resulting over- or under-dosed condition is distressing and can be painful. There is a tendency to blame this increasing sensitivity on the levodopa - which is inaccurate - the on-going loss of brain cells is the real culprit. So what can we do to thread our way through the ever-closing gap between 'not enough' and 'too much' levodopa. My first attempt was a method of recording how I felt (my 'condition') throughout the day. I still use the
graph system, but it became clear to me that there was so much action and interaction going on that just looking at the traces would not produce an understanding of the contributions of the various tablets.

The contribution of the Subject (You)
For a successful analysis, it is essential that careful thought is put into the recording of your condition. This is a personal judgement which only you can make, and the accuracy and consistency of your recordings will ultimately determine the quality of the analysis. I have tried using more objective methods of recording my condition - such as drumming my fingers on the table, but they have all proven to be too coarse to be effective. On the other hand, the object of the exercise is to make you feel good, so having an input parameter which effectively asks "How do you feel ?" seems perfectly logical to me. At the other end of the process, we need to keep a record of what goes into the system (that is, the digestive system) one obvious requirement is the size, type and number of tablets, and the precise time that they were taken. This is quite straight-forward, as you will see in the following sample records.

Understanding and Using the Condition Scale
The Condition scale is numbered from +2 through to -2, with zero being the condition which we are all striving to achieve. Examples of criteria to define these stages of condition are given below, but in general terms it is much more helpful if you regard the +2 to -2 scale as a smooth progression from the +2 condition through to the -2 condition, not as a staircase where the only values are +2, +1, 0, -1 , etc. Remember two things: it does get easier with practice, and 20/20 hindsight is positively encouraged. By all means review the daily result, to ensure that you have used a consistent definition of a particular condition. <HR WIDTH="100%">

Definitions of Conditions:

+2	Strongly Overdosed (Note: not in the dangerous context; merely a condition where you experience severe dyskinesia (random uncommanded movements) or whatever symptom you experience when you have clearly taken too much levodopa. For instance, I spill a lot of beer in this condition! You may find it impossible to sit still, but when you walk your arms and legs tend to go off in different directions. Too much time spent in this condition could produce muscle strains.
+1	Some dyskinesia, but not as distressing as +2. This level represents a condition in which life would be just tolerable: Mild dyskinesia; walking is not too difficult.
0	The end of the Rainbow! Too often this is a condition which you encounter for about 5 minutes as you proceed smartly from an over dosed to an under-dosed condition. It is not difficult to recognise, even after 17 years.
-1	-1 - Mild tremor of the arms or legs, mild muscle stiffness. I can still control the mouse on my computer, but it jumps around a lot. Walking is possible, but there is some tendency to shuffle. As with +1, a condition which you could live with if you had to.
-2	-2 - Your condition with no medication. Severe Tremors and muscular Rigidity. Can only walk with a shuffle. Difficulty getting up from a chair. I spill a lot of beer in this condition too!

As you gain experience, you will find that you feel quite confident giving a condition of say -1.3, or +0.7. With people who have had PD for a considerable time, the changes from over- to under-dosed condition can happen rapidly - between 5 and ten minutes is not unusual.

It is important that you plot the daily record - graph as shown above - just the green line with the circles and crosses. The crosses are readings of condition at times to help define the shape of the trace in periods of time when you did not take medication. More specific depictions and suggestions about preparing the information needed to perform an analysis for you as subject will be found here.

2.0 Program description

2.1 Assumptions

If we arrange things so that a steady flow of levodopa arrives at the brain at just the right rate, this produces the desired optimum result. A water flow analogy might help you visualize this.
Unfortunately, we can only control the quantity of the drug going into our mouth, and it's a long way to the brain. Nevertheless, we assume that there is a relationship between the intake of a tablet and the effect on the brain. After a suitable delay, of course. For instance; if a tablet dumped all of its contents as soon as it was taken, then we might expect to experience a big initial response when the blood with high concentration of levodopa arrived at the brain, followed by a rapid decay in effectiveness.
One additional factor is food, which can make a mess of the most careful drug schedule. The program attempts to make allowances for meals, but only on a rather crude basis (e.g. large meal, small meal)
If we plot the effect of swallowing a tablet as Rate of Flow (mg/hr of Levodopa) versus time, and we have established that the period of effectiveness is say 2 hours, then we can play around with the shape of the flow rate vs time plot bearing in mind that the total area under the curve must always stay constant, as it represents the total quantity of Levodopa in the tablet. It is like a bean bag: if you poke it in here, it will bulge out there. This is the key to the analysis. I thought I had invented this principle of analysis, but I am afraid I have merely re-invented it: a neurologist told me recently that the method is called Pharmacokinetics.
Other Drugs. You will almost certainly be taking additional drugs such as Bromocriptine, Celance (Permax), Ropinerole, and others. These may supplement and enhance the effect of the levodopa, but are not used in this program at present. The effective life of these drugs is usually longer than Levodopa (days instead of hours). They are thus invisible to the analysis. However, if, after having established a baseline when using say 3 Permax, if you then changed to 6 Permax, the analysis could be repeated, and any change attributed to the extra 3 Permax.

2.2 Method of Operation
Assume that the flow vs time plot for each tablet that we take during the day is known to us. We could then just superimpose this shape on the daily record each time that we take a tablet. Some areas-under-the-curve overlap others, so we simply add the overlapping areas together graphically and plot the total. Although we are plotting mg/hour vs time, the shape of this curve should look like our condition plot (on the -2 to +2 scale), so we can arbitrarily factor the mg/hr scale to fit over the condition scale, and we have a working model.

Unfortunately, we do not know the flow vs time plot for each tablet. Indeed, it is probably different for each person, since it depends on that person's digestive system. The program allows me to 'drag' the points on the tablet flow vs time plot around using the mouse pointer . As I change the shape, the plot is re-drawn to keep the area under the curve constant, and the effect on the daily plot can be seen.I have found that this 'manual iteration' technique is very powerful, as it allows the operator's experience and judgement to be integrated into the process. I have found that (within reason) the analysis does converge to a sensible result where the characteristic shape of each tablet is defined; the time delay from taking the tablet to the point when it becomes effective is known; and, we seem to have a good model. We can then try another day's record and see if the same shapes work there.

Out of all that work, the primary value which we want is the flow rate in mg/hr which corresponds to zero on the -2 to +2 scale. When I first did this analysis, it was apparent that the desired flow rate could be achieved almost perfectly by taking one and a half tablets of Madopar Dispersible every 2 hours. The improvement was dramatic, and is still working, although it gets more and more difficult to cope with the disruptive effects of meals.

The reasons why I use Madopar dispersibles are:

They allow fine tuning of the dose, since it is fairly easy to break up a tablet into quarters (12.5 mg/hr of Levodopa)

They are very pleasant to suck like candy, as they contain some vitamin C. When taking tablets every two hours, you can't always find a supply of water to wash them down.

I like to see the pharmacist's face when I go in and present him with a 90-day prescription for 1980 tablets!

An alternative to the above would be to make up a bottle of "liquid Sinemet" (this dissolved tablets solution is described in PARKINSN listserv postings), and then work out how much to drink at each 'tablet time' to get the required mg/hour.

3.0 Explanation
The screen windows picture (above) may need a bit of explanation.

3.1 Main Analysis window. At the top of the screen, running the full width, is the daily record (repeated below), which is a curve fit using the observed results on the -2 to +2 scale. These observed results are plotted in green: a round blob indicates that a tablet was taken at the same time as the condition was noted, and a cross means that no tablet was taken when the reading was made. Id est, the reading condition recorded is made to more precisely define the red line shape. It is important to plot as many condition points as necessary to define the shape of the line.

The black line on this plot shows the output of the model, using tablet characteristics like the one shown in the lower-left window of the computer screen picture above. In the window (plot) shown above are two additional items of interest: the green arrows show the time at which a tablet was taken. The code word beside the arrow denotes the tablet type; e.g. 1.5MD means one and a half Madopar Dispersible. Also, on the X-axis will be seen three blue triangles. These show the times at which meals were taken. You can see the effect about 1/2 to 2 hours later.

27 October 1996 for Brian Collins by Ron Vetter. Go to Ron's homepage.][

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