Parkinson's Disease Tulip


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Old 09-01-2017, 01:51 AM #1
johnt johnt is offline
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Default Levodopa induced dyskinesia (LID)

Levodopa induced dyskinesia (LID) is thought to occur when plasma levodopa levels exceed a patient dependent threshold. So, I have in mind a very simple model of LID. It is based on levodopa plasma levels. There are two important thresholds:
- a lower one, which determines whether a patient is "on" or "off";
- a higher one, which determines whether dyskinesia is present.
Code:
|
|-------------------------- dyskinesia threshold
|   **
|   *  *
|---*----*----------------- "on" threshold
|   *        *
| **               **
|________________________________
Important questions to ask are:
- despite the name, can other dopamine replacement therapies contribute to LID?
- could, for instance a patient whose drug regimen is based entirely on agonists get LID?
The answer in both cases is "yes" [1]:

"while dyskinesia are mainly associated with functional alterations within the basal ganglia pathways related to prolonged exposure to L-DOPA, dopamine agonists and DBS can also cause the appearance of dyskinesia ... some studies have observed the appearance of dyskinesia with the use of dopamine agonists without the concomitant presence of L-DOPA".

In other words, you could in theory at least have a ropinirole induced dyskinesia etc.. Given these thoughts, I think the term LID is misleading in its specificity and it should be broadened to DRID (dopamine replacement induced dyskinesia). Anyhow, because its use is widespread I'll continue to use "LID" even when I'm dealing with other drugs.

Let's look at ways to reduce LID.

Levodopa only approach. Levodopa is in many way is a marvellous drug. A big flaw though, is that it has a short half-life, about 90 minutes. Early in the course of the disease this doesn't matter much, because the body is still naturally producing much of the dopamine that is required, and storing it. In this case, the dose is used as a top-up and fluctuations are low, and don't cross the LID threshold. However, as the disease progresses endogenous dopamine production and storage decreases. At this stage, the dose required to be effective is larger, the fluctuations due to taking discrete doses (typically every 3 to 5 hours) are larger and the chance that these take you over the LID threshold are higher. Dosing every 3 hours to give 3 hours of "on" time per dose, with a drug whose half-life is 90 minutes implies a peak dose 4 times higher than that to just reach the "on" threshold. In some cases, LID may be a response to taking more levodopa than is required in which case a reduction in dose is all that is needed to decrease the LID. A more complex case is where the total levodopa intake is correct, but where the timing of the doses leads to spikes in plasma levels. Taking smaller doses more frequently can decrease the variability in levodopa levels.

Amantadine is reported to have anti-dyskinetic properties. It is a dopamine agonist. The question here is: are amantadine's anti-dyskinetic properties due to anything other than the fact that it is an agonist and the impact that this has on the pharmacokinetics of a patient's drug regimen? As a rough estimate, 100mg of Amantadine IR is equivalent to 100mg levodopa/carbidopa [2]. I will assume this is also true of the ER version (Gocovri). Amantadine IR has a half-life of 16.7 hours [3]. I expect the ER version to have a longer time to reach maximum concentration, but only a slightly longer half-life. As a very gross estimate let's assume that amantadine ER provides a constant level of effectiveness. The study by Pawa et al. [4] used a dose of 274mg. Pawa et al. used amantadine ER in addition to the other dopamine drugs, but I'm more interested in judging the impact of swapping some of the existing levodopa for some dopamine agonist. The average baseline levodopa daily dose was 905.6mg. Now, suppose we replace 274mg of levodopa with 274mg of amantadine. We maintain the LEDD (levodopa equivalent daily dose), while reducing the amount of variability by 274/905.6, approximately one third. The impact of this will be to reduce dyskinesia, the exact amount will depend on the exact features of the LEDD-based pharmacokinetic curve of each patient.

Other drugs. If a long half-life is the only thing special in this context about amantadine, this technique should work for other dopamine agonists and inhibitors. The effectiveness will depend on their half-life compared with levodopa. For instance, although the total impact summed over time of 100mg of levodopa is roughly the same as of 1mg of rasagiline, the effect of rasagiline is much longer lasting, so the maximum concentration, measured in terms of levodopa equivalent dose, of rasagiline 1mg is about one tenth of that of 100mg of levodopa/carbidopa [5].

References:

[1] "Drug-induced dyskinesia in Parkinson's disease. Should success in clinical management be a function of improvement of motor repertoire rather than amplitude of dyskinesia?"
Jean-François Daneault, Benoit Carignan, Abbas F Sadikot, Michel Panisset and
Christian Duval
BMC Medicine201311:76
Drug-induced dyskinesia in Parkinson's disease. Should success in clinical management be a function of improvement of motor repertoire rather than amplitude of dyskinesia? | BMC Medicine | Full Text

[2] "Levodopa Dose Equivalency"
Claire Smith
http://www.birmingham.ac.uk/Document...hLEDReview.pdf

[3] "Comparative Single-Dose Pharmacokinetics of Amantadine Hydrochloride and Rimantadine Hydrochloride in Young and Elderly Adults"
FREDERICK G. HAYDEN,l.2* ANIL MINOCHA,' DANIEL A. SPYKER,' AND HOWARD E. HOFFMAN3
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Aug. 1985, p. 216-221 Vol. 28, No. 2
Comparative single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride in young and elderly adults

[4] "ADS-5102 (Amantadine) Extended-Release Capsules for Levodopa-Induced Dyskinesia in Parkinson Disease (EASE LID Study): A Randomized Clinical Trial"
Rajesh Pahwa, MD1; Caroline M. Tanner, MD, PhD2,3; Robert A. Hauser, MD, MBA4; et al.
JAMA, August 2017
ADS-512 (Amantadine) Extended-Release Capsules for Levodopa-Induced Dyskinesia | Movement Disorders | JAMA Neurology | The JAMA Network

[5] Parkinson's Disease Measurement: PwP, surveys, trials, analysis

John
__________________
Born 1955. Diagnosed PD 2005.
Meds 2010-Nov 2016: Stalevo(75 mg) x 4, ropinirole xl 16 mg, rasagiline 1 mg
Current meds: Stalevo(75 mg) x 5, ropinirole xl 8 mg, rasagiline 1 mg
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Old 09-01-2017, 07:47 AM #2
Nan Cyclist Nan Cyclist is offline
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When I had the plasma infusions, I kept the same Sinemet dosage and developed dyskinesia. Reasoning that I now had too much dopamine in my system, I cut my Sinemet by 20% and the dyskinesia disappeared.
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Old 09-01-2017, 09:53 AM #3
johnt johnt is offline
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Thanks Nan. Your case falls into the category:

"In some cases, LID may be a response to taking more levodopa than is required in which case a reduction in dose is all that is needed to decrease the LID."

I'm glad that you had the confidence to make the change yourself.

My Parkinson's specialist nurse puts my absence of dyskinesia, 12 years after diagnosis, down to my mixed "diet":
5x75mg Stalevo - 500mg LED;
8mg ropinirole controlled release - 160mg LED
1mg rasagiline - 100mg LED
===========================
LEDD = 760mg

It seems to me that Gocovri (amantadine extended release) should only be tried once other methods have failed.

John
__________________
Born 1955. Diagnosed PD 2005.
Meds 2010-Nov 2016: Stalevo(75 mg) x 4, ropinirole xl 16 mg, rasagiline 1 mg
Current meds: Stalevo(75 mg) x 5, ropinirole xl 8 mg, rasagiline 1 mg
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Old 08-24-2021, 03:58 PM #4
maulparking maulparking is offline
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Default tx amantadine info etc. !

John —

Tx for amantadine and pharmacology info! Much appreciated.

I’m a newbie to the site (20210824). PD dx Nov 2009. Sinemet 25-100 x5, (10am-10pm @ 3 hrs), amantadine 100x2. Looking eventually to eliminate amantadine.. (Not asking advice, merely gathering info. ) Ultimately eliminate Sinemet? Before I die, that is. Haha!

Thanks & Cheers

maulparking
“Paul” in CA, USA
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Old 08-30-2021, 03:37 AM #5
johnt johnt is offline
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maulparking,

Welcome to the forum.

It is now 4 years since I posted this thread and 16 years since diagnosis. I'm still on the same drug regimen and doing well(ish). My motor symptoms are OK, I can still walk long distances. But non-motor symptoms have worsened, with speech becoming a problem.

To see how your levodopa levels change with time use:

https://www.parkinsonsmeasurement.or...cokinetics.htm

John
__________________
Born 1955. Diagnosed PD 2005.
Meds 2010-Nov 2016: Stalevo(75 mg) x 4, ropinirole xl 16 mg, rasagiline 1 mg
Current meds: Stalevo(75 mg) x 5, ropinirole xl 8 mg, rasagiline 1 mg
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