One of the problems with levodopa/carbidopa (hereafter called simply "levodopa") is that the drug's short half-life means that it is difficult to get constant levels in the brain. In the first few years after diagnosis this has a limited impact because there are enough surviving dopaminergic neurons to provide a limited reservoir of dopamine (in vesicles) and also to provide a limited endogenous supply of dopamine. Together these mechanisms help smooth out the supply. However, as the disease progresses these safeguards diminish. This leads to pulsatile levels: when the instantaneous supply is too low the PwP is slow and stiff, when the supply is too high there is the danger of dyskinesias.

There is a need, therefore, for a control system that monitors dopamine levels in the brain and releases levodopa in the right amount and at the correct time to reach the brain as required.

I want a practical system:
- one that is non-invasive;
- one that uses bog standard levodopa, taken orally though, perhaps, dissolved in water;
- one that is cheap (no more than $50);
- one that integrates well with my present drug regime.
- one that is available in a few months.

This is what such a system could look like:

1. Start day with a normal dose.

2. Electronics monitors body response every minute, say.

3. Electronics, taking into account recent doses that may still be in the system and previous history, estimates body responses in the next hour, say.

4. If body function is likely to be OK, go to 2.

5. If not, advise taking mini dose (10mg, say).

6. Go to 2.

This is never going to be perfect because gastric emptying times vary and protein levels vary, but, in my opinion, there's a good chance that it would be better than keeping religiously to a fixed schedule of fixed doses.

You will note that it is not intended to measure dopamine levels directly. Rather, some proxy will be used, for instance blink rate or blood pressure variability.

I'll be interested to hear your comments.

John

Bumping this up from a year ago.

This thread ties in with recent posts on:

- levodopa equivalent dose;

- the need to consider the graph of LED for each minute of a dose's "life";

- the advantage of using long lasting drugs, such as rasagiline and controlled release ropinirole and, to a lesser extent, Rytary, to form a baseline load. Immediate release levodopa can then be used to smooth out the peaks and troughs.

- measurement of bradykinesia.

John

From a study posted previously by LabRat

Table 1. Levodopa Equivalent Dose Conversions
Treatment

Dose Conversion Factor

CR = controlled release; ODT = orally disintegrating tablet; LED = levodopa equivalent dose.

1. Levodopa/carbidopa ×1
2. Levodopa/carbidopa CR ×0.75
3. Entacapone ×0.33
4. Tolcapone ×0.5
5. Pramipexole (as salt) ×100
6. Ropinirole ×20
7. Rotigotine ×30
8. Selegiline, oral ×10
9. Selegiline, ODT ×80
10. Rasagiline ×100
11. Amantadine ×1
12. Apomorphine ×10
13. Deep brain stimulation LED × 1.3

To recap, I use the term "dynamic dosing" to mean a drug regimen involving taking variable doses at varying times, from one day to the next. The decision of when to take a dose depends on need and bioavailability.

Dynamic dosing contrasts with the normal dosing regimen, which is static. In a static regimen there is a fixed schedule from day to day e.g. 100mg dose of Sinemet at 0800, 1100, 1400, 1700. Static regimens can become sophisticated, with a PwP using a variety of different drugs with the aim that their combined effect will, due to their differing half-lives, lead to levodopa equivalent levels which are more stable. See:
http://neurotalk.psychcentral.com/thread169655.html

What dynamic dosing means in practice for me is that the timing of my doses during the day is flexible. Even the timing of my initial dose is not fixed: I tend to wake up feeling pretty good and can sometimes go several hours without feeling the need for any drugs. My initial dose of the day serves two purposes: to get "on" as quickly as possible (for which I take 75mg of Stalevo) and to lay down the foundations of a relatively stable base load of long half-life levodopa equivalence (16mg of ropinirole CR and 1mg rasagiline).

My later doses are taken when I feel that I need them. There are several constraints: I will not exceed, except in special circumstances (usually high exercise days) another three 75mg Stalevo pills; I will not take a pill within two hours of a previous dose (this is usually an issue because I have "lost" a dose, due to, possibly, too much protein in a meal); I try to avoid taking a dose within one hour of eating.

The leading indicators that affect the decision of whether or not to take a dose at a particular instant varies from person to person and from time to time. For me, presently, it is an increase in left hand tremor which tells me that I'm about to go "off". But, even if I take the next dose immediately, this warning comes, perhaps, 15 minutes too late to avoid going into a weak "Off" before the next dose takes effect. I also take into account whether I need to "perform" (for instance, go through an airport). If I am, I take the next dose early.

I have been building a computer based system to improve the timing decisions of when to take new doses. My system uses an Arduino micro-controller to pick up readings from an accelerometer placed at the back of the head. (This spot was chosen because it seems to be the best place to identify bradykinesia. The hand is a bad choice for this purpose, because of the arm swing while walking and the prevalence of tremor. Notice that my human control decision is based on tremor, but the computer based system is based on bradykinesia.) The whole package measures 2 x 5 x 7cm. It is fixed inside a hat. The prototype is obtrusive, but any production version would be far smaller, and I think cause few problems.

Are there any other dynamic dosers out there?

John

I've just come across a paper on this very subject [1]. Fisher and Walker write:

"Looking further ahead, Rodriguez‐Molinero et al. ... hypothesised that in the future, body‐worn sensors could be used in conjunction with drug infusion pumps to provide dynamic real‐time dose adjustment in response to both the patient’s disease state and their level of activity."

Reference:

[1] Fisher JM & Walker RW (2013).
"Identification and treatment of wearing off in Parkinson’s disease."
Scottish Universities Medical Journal, 2.2,pp58-63
http://sumj.dundee.ac.uk/data/upload...2i2p.58-63.pdf

John

The pump is now available. The closest thing so far.

The problem with continuous delivery l-dopa is the high cost of the gel form of l-dopa, i've read as high as $65,000/year? so they are only going to be approved as a last resort i assume.

As far as I know, the Duodopa system has no automated real-time dose control.

emc describes [1] the use of the Duodopa system as involving a morning dose, a continuous maintainence dose for 16 hours through the day, and extra "bolus doses" which can be taken as needed. The decision whether or not to use the bolus doses is left to the patient, so in this sense it is a dynamic system.

The advantages of the Duodopa system are:
1. it delivers a continuous dose (1-10ml/hour, where 1ml Duodopa gel is equivalent to 20mg levodopa and 5mg carbidopa) which allows for concentration levels to be more stable;
2. the pump places the drug in the duodenum or upper jejunum, thus reducing the bioavailability uncertainties of the normal, oral approach.

For the person using the normal, oral system immediate release levodopa/carbidopa it is possible to approximate a continuous delivery by taking smaller doses more frequently. Where the available pill sizes are large or where pill cutting is not possible, the pill can be dissolved in vitamin-C and the dose drunk.

I can't find any reference to a trial comparing the performance of high frequency oral dosing of levodopa to the Duodopa system.

Reference:

[1] https://www.medicines.org.uk/emc/medicine/20786

John