Parkinson's Disease Tulip


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Old 05-06-2013, 10:27 AM #1
johnt johnt is offline
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Default High frequency dosing

Has anyone tried to improve the effectiveness of their immediate release levodopa based drugs by taking the drug more frequently, while reducing the dose to maintain the total dose for the day at the original level?

For example, a total of 300mg of levodopa per day could be delivered by 3 doses of 100mg, 4 doses of 75mg, 10 doses of 30mg, 100 doses of 3mg, etc..

More frequent doses should even out the amount of levodopa in the body. But, as always, the devil is in the detail.

John
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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 05-06-2013, 11:14 AM #2
soccertese soccertese is offline
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John, that is the challenge of carbidopa/levodopa. i'm sure your're aware that one way to do that is to dissolve your daily total dosage in water plus vitamin c, i think 500mg but probably not that critical and take it in liquid form. i haven't tried to do that even though i do have to take L/C every 3 hrs most of the time., maybe more often and that's all i take, both IR and CR, i still play around with he doseage everyday. lately i've been taking 125mg 1st thing in the morning (split a 25/250 IR) and take another 125 2hrs later, my theory is i need to replenish my depleted levodopa quickly and also the carbidopa, it also has a short half life. when calculating my total levodopa for the day, i modify 200mg CR to be bioequivalent to 120mg levodopa.

i can play around with my meds since i don't work, if i had a job and/or was a caregiver, i'd have to take my meds on a tight schedule. at that point, would likely take 125mg L/C upon wakening and then a 1.5 tabs of 50/200mg CR an hr later and develop some variation on that the rest of the day.
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Old 05-06-2013, 02:18 PM #3
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It seems to me that there is much that we can do to improve the effectiveness of existing drugs.

I have posted [1] on the effect on me of drinking Stalevo in ascorbic acid (vitamin C). This test showed a slightly faster response and a higher bio-availability than from taking the Stalvo normally. Clearly, one test of each form of delivery is insufficient to generalize from, but it certainly warrants further investigation.

Once you can drink the drug frequent dosing becomes practical: e.g. 100 sips during the day. At its simplest the equivalent of each pill could be put into a small bottle. To raise levodopa levels at the start of the day, one bottle could be drunk quickly, then the other bottles sipped during the day. A more advanced system could monitor the amount being drunk and recommend when to take more. This could be refined further by monitoring patient symptoms and adjusting the recommendations accordingly.

It is surprising that there is so little reporting of high frequency dosing. An exception is Palhagen who got PwP to drink their medications during the day [2]:
"After achieving an optimal dosing regimen, the nasointestinal tube was removed and the LCIG [levodopa/carbidopa intestinal gel] dosing schedule was converted to an oral treatment regime that PwPs could administer themselves by sipping or drinking the dissolved medication. This allowed for division of the daily-prescribed quantity into smaller, more frequent doses throughout the day."

A major disadvantage of the liquid medication method compared with the intestinal pump is that there is a delay in the delivery of the "drink" to the intestines. Are there other disadvantages?

Reference

[1] http://neurotalk.psychcentral.com/thread183360-2.html

[2] "The Dose-Finding Study nasoduodenal infusion of levodopa/carbidopa intestinal gel (LCIG, Duodopa®) as a dose-finding tool in parkinsonian patients with fluctuations"
Palhagen S.
European Parkinson's Disease Association
http://www.epda.eu.com/ru/parkinsons...finding-study/

John
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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 05-06-2013, 02:37 PM #4
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i've read about frequent dosing using "liquid" sinemet in a number of general books on pd, one being "THE PARKINSON'S DISEASE TREATMENT BOOK" and a general procedure on calculating sinemet dosage. in all cases, they just recommend storing the mixture in a bottle with measurements marked on the side and pouring out the correct amount or having a cup with the correct volume marked on it. i imagine it is a hassle having to mix the stuff up daily and if you make a mistake can be problematic. not sure if you need to refrigerate it. seems L/C dissolves so readily and is easy enough to split you can take small amounts without having to dissolve it.
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Old 05-06-2013, 08:10 PM #5
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Quote:
Originally Posted by soccertese View Post
i've read about frequent dosing using "liquid" sinemet in a number of general books on pd, one being "THE PARKINSON'S DISEASE TREATMENT BOOK" and a general procedure on calculating sinemet dosage. in all cases, they just recommend storing the mixture in a bottle with measurements marked on the side and pouring out the correct amount or having a cup with the correct volume marked on it. i imagine it is a hassle having to mix the stuff up daily and if you make a mistake can be problematic. not sure if you need to refrigerate it. seems L/C dissolves so readily and is easy enough to split you can take small amounts without having to dissolve it.

What would this have to offer over an extended release formulation? Isn't the effect the same, you're getting a constant feed of the drug instead of large amounts?


Or does the CR not keep the blood concentration high enough and mini bolus administrations are preferred?
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Old 05-07-2013, 07:40 AM #6
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Hammilton, quite rightly asks what frequent dosing has "to offer over an extended release formulation?"

Controlled release drugs have a role to play: they can get you near the right level of drug concentration and hold it there for several hours.

For patients with functioning dopaminergic neurons excess levodopa can be stored, converted into dopamine and released as required later. In this way the peaks and troughs can be levelled off to a large extent.

As the disease progresses dopaminergic neurons die off or cease to function correctly. The storage capacity is, therefore, lost. This leaves you following plasma levels of levodopa: too little and you are "off", too much and dyskinesia can occur.

At this stage, the longevity of the controlled release drug counts against it; it's been taken and will continue to deliver levodopa regardless of the present requirements.

Another problem is that most drugs come in a limited number of strengths. It will be rare for a person's requirements, based on body weight, diet, exercise etc., to be optimally met by one of the strengths available.

Let's make a rough estimate of the size of the discrete strength error. For instance, Stalevo comes in six strengths: 50, 75, 100, 125, 150, 200 mg levodopa. Suppose you relied only on one 100 mg pill taken four times per day, making no adjustments. And assume this really was the best strength for you to take. Roughly speaking this means that your real need lies between 87.5mg (half way between the strength you take and the strength below) and 112.5mg. So, the error goes from 0 to 12.5mg, giving an average error of approximately 6%.

High frequency dosing allows adjustments to be made to fit patients' requirements.

John
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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 05-07-2013, 08:07 AM #7
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john,
i'm sure people use "liquid" sinemet. duopdopa reducing dyskinesias and improving quality of life obviously shows the advantages of keeping the blood levels of levodopa constant, that's why there is also the development of another israeli levodopa pump that administers levodopa directly into the blood and not the small intestine and other CR levodopa/carbidopa formultions, rytary being one and i think there is another one in phase2/phase3?

i can only speak for L/C CR, i've never taken stalevo, but if it was doing the job, these other drugs/technology wouldn't be in development. agonists have a much longer half life, it seems if one can tolerate one why not just add an agonist to smooth out the fluctuations? there is work on new agonists and formulations that go under the skin and give months of drugs. i have to wonder how the neupro patch is doing now that it's back on the market?

i've read many accounts and personally experienced some unpredictability of CR but i'll always take it when i have to be at my best kind of as insurance that i'll have enough dopamine and in case i forget to take a dose.

as far as limited strengths, one can split a 100mg L/C into 25mg sections with pretty good accurracy and a 250mg into 62.5mg chunks so at the minimum, if the tablets are scored you have at the minimum 25mg chunks to play around with if you start with the 100mg tablet, they do though crumble a little when split that much. i've read the 200mg CR retains it's slow release feature if split..

i think the greater problem is absorption due to diet and "gremlins". sometimes my LC just doesn't seem to get absorbed.
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Old 05-07-2013, 09:10 AM #8
Jim091866 Jim091866 is offline
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Default taking a little bit more often

for about the last year I have taken my immediate release 25/100 one and a half every 2 hours. This way i stay pretty much on and dont have dyskinesia. The only problem is the discipline to take the pill when my timer goes off, it's easy to go another 20 -30 mins. If I fall asleep and take a nap I usually miss a dose but I think that because I have a dose always in my system it recovers much easier. I also have to remember that more (2 tablets) does not get on board any faster, it just puts me over the edge towards dyskinesia. Seems to work for me.
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Old 05-10-2013, 11:47 AM #9
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I'd like to discuss intestinal delivery systems, e.g. Duodopa, within the context of high frequency dosing.

It seems to me that both have the same objective: reduce fluctuating levodopa levels

As I see it, intestinal delivery systems have two advantages:
- continuous delivery, taking very high frequency to the limit;
- more rapid response, being downstream changes to the dose are effective more rapidly.

The major disadvantages are the need for surgical intervention, the current unavailability for some of us, and cost.

Intestinal delivery systems are intended for people for whom current medication gives poor control over their Parkinson's symptoms. It would be interesting to know how many people who are keen on going down the intestinal pump route, are currently not optimally medicated. I suspect that many would no longer want the surgery if they were optimally medicated using existing techniques.

John
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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 06-19-2017, 05:45 AM #10
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Microtablets

Aquilonius and Nyholm write [1]:

"A rapidly soluble tablet formulation containing 5 mg levodopa and 1.25 mg carbidopa was developed (LC-5, named Flexilev® in Sweden)."

"in a cross-over study in healthy volunteers, fractionation of levodopa with Flexilev as compared to standard administration of levodopa/carbidopa/entacapone decreased the fluctuation index of both levodopa and carbidopa in plasma by nearly half ... We have recently confirmed the similarity in levodopa pharmacokinetics in healthy volunteers and PD patients under fasting conditions".

I think the dispensing system is overly complicated, but the microtablets themselves will prove useful.

Reference:

[1] "Development of new levodopa treatment strategies in Parkinson’s disease—from bedside to bench to bedside"
Sten-Magnus Aquilonius and Dag Nyholm
Upsala Journal of Medical Sciences, 2017
Development of new levodopa treatment strategies in Parkinson’s disease—from bedside to bench to bedside

John
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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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