Coastal Neurological
Medical Group, Inc.

New Concepts in the Treatment of Parkinson's Disease with Emphasis on COMT Inhibition
BY DEE SILVER M.D.

L-dopa has been the gold standard for the treatment of Parkinson's disease for many years and when it was introduced it revolutionized the treatment of Parkinson's disease. It has been the most efficacious drug symptomatically and it has definitely improved activities of daily living, survival; but some of the undesirable effects of using L-dopa with long-term use are its associated motor complications. As the Parkinson's disease progresses there is greater loss of striatal nigral neurons. In early disease there is a generally smooth response to the use of L-dopa and there are usually no dyskinesias and there is very little off time, if any.

As the disease becomes more advanced, there is diminished duration of clinical improvement and there is an increased incidence of dyskinesias and motor complications. Then, as the disease is more advanced, there is unpredictable response, there are sudden offs, unpredictable offs and dyskinesias, both peak and diphasic, that are oftentimes difficult to predict. When a patient is on L-dopa only there are numbers of techniques that can be used to try to improve the symptoms. Most patients now are being treated with dopamine agonists early and most of the patients will already have dopamine agonists as one of their medications and usually it will be a high dosage. When symptoms start to re-emerge then the L-dopa dose can either be increased in the total individual dose amount or more frequent dosing can be used, or controlled release levodopa can be used, or more of the dopamine agonists can be tried, or COMT inhibitors such as Comtan can be used. Carbidopa was added to L-dopa to allow for the blocking of the dopamine decarboxylase enzyme that allowed L-dopa to be metabolized to dopamine in the periphery or in the plasma. This allowed more L-dopa into the brain but it was still a very small percentage of the total plasma amount. Then, COMT inhibition became available, first with Tasmar and then with Comtan. Tasmar is used very little at the present time because of liver side effects, but Comtan is widely used and it blocks the plasma COMT pathway to 3-O methyldopa. This takes place in the periphery and is thought not to take place significantly in the brain. This allows a greater amount of L-dopa to go from the plasma to the brain, maybe as high as 10%. Entacapone{Comtan} has some very consistent pharmakinetics and it is rapidly absorbed with a T-max of 1 hour, has a half-life of about 1/2 hour and food does not affect the pharmakinetics. It is highly protein-bound but there is no displacement of other highly bound protein drugs such as warfarin or Coumadin. Metabolism is 90% in the liver and 10% by the kidney. There has not been any significant hepatic toxicity noted with Comtan.

As Parkinson's disease progresses from a disease in which there is very little wearing OFF or morning OFF, to a point in time where there is significant wearing OFF and then major motor complications with ON/OFF and sudden OFF and unpredictable OFF, there need to be strategies to help the Parkinson patient have a smoother clinical course with less motor complications. One of these strategies is using Comtan to help prolong the half-life of L-dopa peripherally. It can do this by about 85% from 1.5 hours up to about 2.25 hours. This enhances the amount of L-dopa in the plasma for a longer period of time and allows more available L-dopa into the brain. In studies, this can be correlated with improved motor function and scores on the UPDRS. There have been numbers of studies done using Comtan. One study is called the NOMECOMT study which had an extension study called the NOMESAFE extension. There was also the SEE-SAW study and the CELOMEN and the UK Irish study. All of these studies showed improvement of ON time and reduced OFF time in Parkinson patients. In the NOMECOMT trial there was a significant improvement in OFF time by about 1.3 to 1.5 hours. There was improved OFF time by a mean % improvement at 24 weeks of about 17% over placebo. Comtan also improved the motor function and activities of daily living of patients as compared to patients on placebo. Improvement in the scores were as high as almost 5 on the UPDRS. There was also in this study the ability to reduce the amount of levodopa dose per day. It was thought that it was about 100 mg a day reduction on average. There was an extension study called the NOMESAFE study, which followed patients for 3 years using entacapone at 200 mg administered to patients on L-dopa. The number of patients followed was 132 and more than 90% of patients taking the Comtan had maintained or improved OFF time after 3 years. This was important because it showed that the patient stabilized as far as their amount of OFF time for the 3-year duration of the study. It also documented that at 3 years there was still a reduction in the amount of L-dopa; at 3 years it was reduced by 41 mg. This was not as much of a reduction as when the study was conducted for 26 weeks but this was a 3-year evaluation and the reduction was 41 mg. Most importantly, comparing the 3-year evaluation and baseline data, performance of activities of daily living and motor function was maintained after 3 years. In the NOMESAFE trial there was a washout period and it showed that when the drug was washed out there was a significant deterioration in duration of benefit and in activities of daily living and an increase in the L-dopa dose. In using an impression of general improvement called the Global Impression Scale, 64% of the patients were improved at the end of 3 years, 24% were unchanged and only 12% declined. Adverse events were mainly those that were dopaminergic and only 18% of the patients discontinued the study because of adverse events. There was no evidence of liver toxicity in this NOMESAFE trial. It showed, without question, that Comtan was a good drug to use to maintain long-term treatment in patients on L-dopa and that when the drug was discontinued or withdrawn the patient worsened. The safety profile was very good.

A German-Austrian study called CELOMEN trial used 301 patients, most of whom had end-dose failure but some were non-fluctuating (meaning they had no morning off, end-dose failure, dyskinesias, or on/off). These patients were studied in a randomized double blind parallel group and it was found that the amount of ON time significantly improved percentage-wise and that OFF time significantly reduced. It also showed that there was improvement again compared to placebo in the UPDRS scale, as high as 4 points. A UK-Irish study evaluated 300 patients in a double blind randomized placebo controlled parallel group study and 57% were fluctuating patients (with motor complications, dyskinesias, wearing off) and 43% were non-fluctuating. Again, in this group it was shown that there was some improvement in patients with entacapone as compared to baseline. This occurred in fluctuating and somewhat in non-fluctuating patients. The increased ON time for the UK-Irish study was 1.3 hours; for the CELOMEN trial it was increased in on time 1.7 hours. There was also some reduction in the amount of L-dopa for the entacapone patients and an increase in the patients who were on placebo. These two studies that used non-fluctuators brought up the concept of using entacapone early in non-fluctuating patients.

Dr. Peter Jenner has done a numbers of animal trials using MPTP marmosets and he has done this using L-dopa with and without entacapone at various doses. The rationale for using the animal model trials was to see if there was an advantage in using entacapone with more frequent dosing of L-dopa in allowing a smoother response to the medication and to reducing the amount of dyskinesias and improving locomotor function.

The concept of continuous dopaminergic stimulation is a hypothesis that brings about the concept of pulsatile stimulation at the post-synaptic receptor sites. This is due to the progression of the disease, the loss of striatal nigral neurons, the loss of ability to buffer the dopamine and the short half-life of L-dopa. It is thought that short half-life L-dopa leads to fluctuating plasma levels of levodopa and high and low levels of receptor activation. Smoothing out the levodopa availability allows for more continuous dopamine stimulation at the post-synaptic receptor sites and hopefully delaying or preventing the onset of motor complications. Dr. Jenner did animal work that showed when comparing L-dopa to the dopamine agonists there was a greater likelihood of developing dyskinesias if you used L-dopa as compared to the dopamine agonists in MPTP monkeys. Even if the dopamine agonist had L-dopa added to it there was still less development of dyskinesias as compared to the animals only given L-dopa. This supported the concept of continuous stimulation because of the longer half-life of the dopamine agonist. When the pramipexole, ropinirole and pergolide clinical trials were finished it became clear that clinically dopamine agonists when used as monotherapy had a dramatic reduction in the development of dyskinesias as compared to those patients who were on L-dopa. This was also seen even though there was added L-dopa to the dopamine agonists. There was still a robust reduction in the development of dyskinesias as compared to L-dopa alone.

Dr. Peter Jenner used the MPTP primate study model and used multiple dosing of levodopa with and without entacapone. He used levodopa twice day alone and with entacapone and he used levodopa four times a day with and without entacapone in his animal models. What he showed was that when using entacapone there was a smoother response and there were fewer fluctuations in the motor response when these animals were observed. He then monitored disability scores and showed that there was less disability when the animals were given levodopa four times a day with entacapone and the duration of the anti-Parkinson activity was much more prolonged when levodopa was four times a day with entacapone as compared to any of the other dosing. He also noted that these animal models showed less dyskinesia when the L-dopa was given four times a day with entacapone as compared to L-dopa four times a day alone, or even L-dopa twice a day with entacapone or L-dopa just twice a day.

Hence, it does appear, as has been thought by many, especially Dr. Jenner, that using animal models of the MPTP animal model type can predict the results of human clinical trials. That appears to be the case in the study of COMT inhibition in animals and conclusions of the COMT clinical trials.

COMT inhibition (Comtan) has shown that it is beneficial in treating wearing OFF or end-dose failure in patients and that it can reduce OFF time, improve ON time and that there is significant safety with the use of this drug as documented by the 3-year extension study. An important consideration at the present time is whether entacapone should be used early in the treatment of Parkinson's disease giving the drug with levodopa initially or very soon after L-dopa is given to the Parkinson patient. This would be done with the theoretical consideration that with the combined usage at multiple doses per day there would be a more physiological dopamine stimulation which would be giving more continuous dopamine stimulation at the post-synaptic receptor site and theoretically avoiding or delaying levodopa motor complications.

The main points to be considered are that drugs are evaluated by using the concept of the triangle, which has efficacy, tolerability and safety at each corner of the triangle. Efficacy has a long-term consideration and a short-term consideration. Comtan certainly is tolerable. It is definitely safe and its efficacy has been proven in clinical trials. The question is whether long-term efficacy can be enhanced by giving the drug at the time of initiation of L-dopa or shortly thereafter. The future use of Comtan is being strongly considered in non-fluctuating patients as well as patients that are fluctuators who have end-dose failure, wearing off and need more on time and less off time.

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9850 Genesee Avenue
Suite 860
La Jolla, CA 92037
Tel: 858.453.3842
Fax: 858.535.9390

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