Parkinson's Disease Tulip


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Old 11-05-2016, 05:34 PM #1
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Default Inhaler for Levadopa

I was curious where the inhaled levadopa for off periods was hiding and found this 3 week old article....

A Levodopa Inhaler for Parkinson’s? | ALZFORUM
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Old 11-05-2016, 09:10 PM #2
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Originally Posted by eds195 View Post
I was curious where the inhaled levadopa for off periods was hiding and found this 3 week old article....

A Levodopa Inhaler for Parkinson’s? | ALZFORUM
There are two different phase 3 trials ongoing right now. They should complete during 2017. I don't forsee any problems getting the NDA approved by the FDA. However, that will likely not be until 2018. Keep in mind that this will be approved as a secondary, recovery drug. It won't be indicted or available for primary treatment.
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Old 11-05-2016, 09:26 PM #3
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For some reason I thought this was a 5-10 minute rescue drug if someone freezes up, but my neuro thought it could last an hour. If he is right, that would be huge as it would bridge the gap between doses while one waits for their primary meds to kick in. Not bad for a secondary source of relief.....
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Old 11-06-2016, 10:46 AM #4
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Originally Posted by eds195 View Post
For some reason I thought this was a 5-10 minute rescue drug if someone freezes up, but my neuro thought it could last an hour. If he is right, that would be huge as it would bridge the gap between doses while one waits for their primary meds to kick in. Not bad for a secondary source of relief.....
Your neuro is correct. It takes 5 - 10 minutes for CVT-301 to become "effective". It can then last for at least an hour and possible longer (the trial was only designed to test effectiveness up to an hour after). CVT will be indicated (if and when approved) for the episodic treatment of "off" periods. This is a somewhat expanded indication than that of a rescue drug similar to apomorphine injections. The idea is to smooth the transitions between the on and off periods of normal treatment protocols.
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Old 11-07-2016, 01:50 AM #5
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Therapies that give PwPs better control of levodopa levels (and, hence, dopamine) are to be welcomed. But I do have a number of concerns about the levodopa inhaler's practical use.

A PwP suffering regular "off" periods is likely to be under-medicated. The fact that this state of affairs has been allowed to occur indicates poor medical management of the disease. For instance, a typical 6 monthly schedule of visits to the neurologist is too infrequent for some PwP to be able to titrate doses upward fast enough as required by the progression of the disease. The inhaler may help, but it would seem better to solve the problem by conventional means, by increasing the dose or increasing the frequency of the doses.

Irregular off periods may be caused by interactions with foods, especially proteins, and the timing of gastric emptying. The inhaler has more of a role to play here. But one problem is that, at least for me, sometimes the effect of a dose is delayed, but does come eventually. The danger is that a PwP may use the inhaler just before the original dose kicks in, which combined will result in very high levodopa levels.

I am also concerned that the more rapid response to a dose may increase addiction levels.

Talking generally, the pharmacokinetic/pharmacodynamic model which seems to fit my own symptoms is that I have a threshold of levodopa plasma levels, below which I am "off" and above which I am "on". Unfortunately, levodopa has a short half-life (about 90 minutes) so if the dose is just large enough to get you to the threshold, but not beyond, the decline back below the threshold would end the "on" just as soon as it started. To get longer "on" times using plain C/L requires taking a dose which results in levels well above those necessary to get to the threshold. For instance, taking a dose which takes you to plasma levels twice that required to get "on" gives you an "on" duration equal to the half life. This leads to varying levodopa levels, which is undesirable. Alternatively, you must increase the frequency of the doses or find some way of increasing reservoirs of dopamine.

See my web page:
Parkinson's Disease Measurement: PwP, surveys, trials, analysis
You input the drugs that you use each day and the program draws graphs of how plasma levels vary over time.

John
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Current meds: Stalevo(75 mg) x 5, ropinirole xl 8 mg, rasagiline 1 mg
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Old 11-07-2016, 09:36 AM #6
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[QUOTE=johnt;1228202]Therapies that give PwPs better control of levodopa levels (and, hence, dopamine) are to be welcomed. But I do have a number of concerns about the levodopa inhaler's practical use.

A PwP suffering regular "off" periods is likely to be under-medicated. The fact that this state of affairs has been allowed to occur indicates poor medical management of the disease. For instance, a typical 6 monthly schedule of visits to the neurologist is too infrequent for some PwP to be able to titrate doses upward fast enough as required by the progression of the disease. The inhaler may help, but it would seem better to solve the problem by conventional means, by increasing the dose or increasing the frequency of the doses.

Irregular off periods may be caused by interactions with foods, especially proteins, and the timing of gastric emptying. The inhaler has more of a role to play here. But one problem is that, at least for me, sometimes the effect of a dose is delayed, but does come eventually. The danger is that a PwP may use the inhaler just before the original dose kicks in, which combined will result in very high levodopa levels.

I am also concerned that the more rapid response to a dose may increase addiction levels.

Talking generally, the pharmacokinetic/pharmacodynamic model which seems to fit my own symptoms is that I have a threshold of levodopa plasma levels, below which I am "off" and above which I am "on". Unfortunately, levodopa has a short half-life (about 90 minutes) so if the dose is just large enough to get you to the threshold, but not beyond, the decline back below the threshold would end the "on" just as soon as it started. To get longer "on" times using plain C/L requires taking a dose which results in levels well above those necessary to get to the threshold. For instance, taking a dose which takes you to plasma levels twice that required to get "on" gives you an "on" duration equal to the half life. This leads to varying levodopa levels, which is undesirable. Alternatively, you must increase the frequency of the doses or find some way of increasing reservoirs of dopamine.

See my web page:
Parkinson's Disease Measurement: PwP, surveys, trials, analysis
You input the drugs that you use each day and the program draws graphs of how plasma levels vary over time.

John[/QUO

bottom line, advanced pd'ers with optimized drug dosing need a better rescue option than injectable apomorphine, especially those that are only on C/L. There is also a sublingual apomorphine strip which i believe will soon be approved. It would be interesting to see how quickly one goes on taking this inhaled l-dopa after eating >20 grams of protein. it still has to compete with all those amino acids to get into the brain. wonder if apomorphine is absorbed differently. i guess checking if there is protein interference with duodopa gel would shed light on this.
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Old 11-07-2016, 10:06 AM #7
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My biggest difficulty in keeping my dopamine level comes from dyskinesia, so yes I would say I'm under-medicated in one sense. After eleven years on levodopa /carbidopa, I can't increase the dose because the dyskinesia becomes too severe. I walk a very fine line between not enough so I have freezing until the next dose kicks in, or taking enough so I don't freeze but end up with dyskinesia. My MDS told me a couple of years ago that he could help me with the freezing or the dyskinesia but not both. He suggested Amantadine but I'm not ready to put up with those side effects yet.

I'm becoming more and more dedicated to Dr. Alberts cycling program - it makes a difference in how long the meds last, and more interesting, it makes a difference in how mobile I am when I'm up at night. So it must be having some effect on how much dopamine I'm producing myself since I don't take any meds for about 12 hours from my last dose at 7:00 or so.
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Old 11-07-2016, 10:59 AM #8
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Quote:
Originally Posted by johnt View Post
Therapies that give PwPs better control of levodopa levels (and, hence, dopamine) are to be welcomed. But I do have a number of concerns about the levodopa inhaler's practical use.

A PwP suffering regular "off" periods is likely to be under-medicated. The fact that this state of affairs has been allowed to occur indicates poor medical management of the disease. For instance, a typical 6 monthly schedule of visits to the neurologist is too infrequent for some PwP to be able to titrate doses upward fast enough as required by the progression of the disease. The inhaler may help, but it would seem better to solve the problem by conventional means, by increasing the dose or increasing the frequency of the doses.

John
I have to respectfully disagree with you on much of what you stated. Multiple studies have shown that about 50% of PWP report they have periodic "wearing off" phenomenon after anywhere for 5 - 10 years. It is as high as 80% for later stage patients. When I was presenting at the FDA last year, they had research that showed that many patients consider the inability to smoothly control their motor fluctuation symptoms as the worst problem they have. At the WPC in September I was in meetings where practically every person there said they experience periodic "wearing off" and motor fluctuation. Sure, PWP need to constantly be adjusting their medication protocols and timing. But, controlling the "off" phenomenon goes way beyond that. A great example is exactly what you said about the outside variables, such as what and when we eat, interacting with the on-off cycle. This fact alone means that people will experience periodic offs.

With regard to "addiction", this inhalable formation has been tested now on hundreds of PWP, many who have been on it now for several years. There is absolutely no evidence of "addiction" to date. However, even if it were, I would guess that those people that I've met who experience severe on-off fluctuations would choose to still use a quick and easy solution rather than to continue suffering. As Soccertese said, "advanced pd'ers with optimized drug dosing need a better rescue option than injectable apomorphine", which is currently the only available option. Sublingual apomorphine will be available soon (likely FDA approval), and that will give PWP another option. However, there seems to be more side effects with that as opposed to the levodopa inhaler. Both will be a good addition for mid to late stage PWP.

Last edited by Tupelo3; 11-07-2016 at 11:27 AM.
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Old 11-08-2016, 01:54 AM #9
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Wendy,

You write:
"I walk a very fine line between not enough so I have freezing until the next dose kicks in, or taking enough so I don't freeze but end up with dyskinesia. My MDS told me a couple of years ago that he could help me with the freezing or the dyskinesia but not both."

Have you tried reducing the time between doses? Your first dose of the day would be unchanged, the subsequent doses, because they come earlier and, therefore, have a higher starting point, may need to be lower. You may need to fit another dose in. In this way you might be able to have a net increase in your daily levodopa dose without increasing your CMAX, thus decreasing "off" time, while avoiding dyskinesia.

I'm also 11 years after diagnosis and get up in the morning feeling fairly good, sometimes going hours without taking my meds. I too put this down to some continued endogenous dopamine production and storage.

John
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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 11-08-2016, 09:58 PM #10
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Thanks for your answer, John. I have considered a smaller more frequent dose but I'm trying so many different things to improve my PD symptoms that I just haven't got to that yet. I'll think more about it - it would probably make a difference more rapidly than diet or exercise.

Right now I take 1.25 mg of Mirapex three times a day and 1.3 tabs of levodopa/carbidopa 100/25 every three hours. Except for my last dose at 7:00 pm when I've cut back to 1.0 mg and 1.0 tab to try to reduce the early evening dyskinesia which is the worst

What would you suggest as a trial of a smaller dose? I' very aware you're not a Dr but you must have tried this for yourself and I'd appreciate hearing about what you did and how it worked out.

Wendy
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