Better therapy for Parkinson's disease

Current therapy

The movement disabilities due to Parkinson’s disease result from loss of the dopamine producing cells which supply dopamine to the striatum of the brain. 

Administering dopamine to patients is ineffective as dopamine does not cross the blood brain barrier. Instead patients are treated with L-DOPA. L-DOPA can cross the blood brain barrier and is converted in the brain to dopamine by AADC.

L-DOPA was first used to treat Parkinson’s nearly 50 years ago and still remains the most effective treatment for PD.

Other agents such as  dopamine agonists  (pramipexole or ropinirole), COMT Inhibitors (entacapone or tolcapone) or (MAO-B inhibitors  selegiline  or rasagiline ) alone or in combination with L-DOPA. However none of these agents is as effective as L-DOPA.

Almost all patients eventually require L-DOPA.

Initially L-DOPA is very effective and usually well tolerated.


Chaotic blood (and brain) levels

L-DOPA shows particular pharmacokinetics. Absorption across the bowel wall (and the blood brain barrier) is by a saturable facilitated transport system shared with other large neutral amino acids. Therefore absorption varies markedly depending on what the patient has eaten. Drug transport from plasma to the brain is mediated by the same carriers operating in the intestinal mucosa. 

L-DOPA plasma half-life is very short (approximately 90 minutes), resulting in marked plasma drug concentration fluctuations. 

Longterm exposure to the fluctuating L-DOPA level leads to swings in the therapeutic response (“wearing-off”, “on-off fluctuation” and episodes of “freezing”) and the development of L-DOPA induced dyskinesiaContin

L-dopa plasma concentrations for patients taking L-dopa/carbidopa 100/25 mg standard-release tablets  every 2 hours. Stocchi

On-off variation

The on-off phenomenon is an unfortunate problem in the treatment of Parkinson’s disease, and while some people may notice it early on in starting L-DOPA, most notice it within three to five years.

When the level of L-DOPA causes an optimal level of dopamine in the brain, the patient is able to move and speak well. The patient feels well and is described as “on”. At other times however movement is impaired and speech may be slurred. This is the “off” phase. Initially this is managed by increasing the number of times a day when L-DOPA is administered, however over-time, control become more erratic and the patients spends greater proportions of the day “off”

Freezing of gait (FOG)

Freezing is an uncontrolled and temporary inability to move which may last just a few seconds or sometimes several minutes. This tends to happen suddenly, particularly when walking, as if the feet have become stuck to the ground. Speech, writing or opening and closing the eyes can also be affected. 

Patients may find it difficult to judge spaces or go through narrow entrances or doorways. It can also be difficult to move from level to uneven ground or from a plain to a patterned walking surface.

Freezing tends to be more frequent as Parkinson’s progresses particularly if you take levodopa. It is less common in early Parkinson’s and if the patient has not taken L-DOPA.

Many people experience freezing when they are ‘off’ but freezing and ‘off’ periods are not the same and require different management. If a person freezes this will only affect certain movements, whereas if they are ‘off’ all movements will be difficult. Parkinson’s Europe

Freezing causes falls, mobility restrictions, and poor quality
of life.

Video from youtube – Lancet TV

L-DOPA induced dyskinesia (LID)

10% of patients per year treated with oral L-DOPA will develop dyskinesia. After 5 years 50% of patients will have developed L-DOPA induced dyskinesia.

Dyskinesia can involve one body part, such as an arm or leg, or the entire body. It can look like fidgeting, writhing, wriggling, head bobbing or body swaying. Dyskinesia tends to occur most often during times when other Parkinson’s symptoms, such as tremor, slowness and stiffness, are well controlled. (“on with dyskinesia”) Feeling stressed or excited also can bring out dyskinesia. Some people say they prefer dyskinesia to stiffness or decreased mobility. Others, though, have painful dyskinesia or movements that interfere with exercise or social or daily activities.

Video from YouTube.