L-DOPA is used to replace dopamine lost in Parkinson's disease because dopamine itself cannot cross the blood-brain barrier where its precursor can. However, L-DOPA is converted to dopamine in the periphery as well as in the CNS, so it is administered with a peripheral DDC (dopamine decarboxylase) inhibitor such as carbidopa, without which 90% is metabolised in the gut wall, and with a COMT inhibitor if possible; this prevents about a 5% loss. The form given therapeutically is therefore a prodrug which avoids decarboxylation in the stomach and periphery, can cross the blood-brain barrier, and once in the brain is converted to the neurotransmitter dopamine by the enzyme aromatic-L-amino-acid decarboxylase.

Side Effects

Possible side effects include:

Hypotension, especially if the dosage is too high.
Arrhythmias, although these are uncommon.
Nausea, which is often helped by taking the drug with food, although protein interferes with drug absorption.
Gastrointestinal bleeding.
Disturbed respiration. This is not always harmful, and can actually benefit patients with upper airway obstruction.
Hair loss.
Confusion.
Extreme emotional states, particularly anxiety, but also excessive libido.
Vivid dreams and/or fragmented sleep.
Visual and possibly auditory hallucinations. It can reveal dementia that was previously subclinical.
Effects on learning. There is some evidence that it improves working memory, while impairing other complex functions.
Sleepiness and sleep attacks.
a condition similar to amphetamine psychosis.

Although there are a number of side-effects associated with L-DOPA, particularly psychiatric ones, it has fewer than other Parkinson's drugs, including anticholinergics, selegiline, amantadine, and dopamine agonists.

More serious are the effects of chronic L-DOPA administration, which include:

End-of-dose deterioration of function.
On/off oscillations.
Freezing during movement.
Dose failure (drug resistance).
Dyskinesia at peak dose.

Clinicians will try to avoid these by limiting L-DOPA dosages as far as possible until absolutely necessary.

Synthesis

L-Dopa is produced from the amino acid tyrosine by the enzyme tyrosine hydroxylase. It is also the precursor molecule for the catecholamine neurotransmitters dopamine and norepinephrine (noradrenaline), and the hormone epinephrine (adrenaline). The prefix L- references its property of levorotation (compared with dextrorotation or D-DOPA).

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Medication may improve symptoms in Parkinson's disease
From American Family Physician, 11/1/05 by Anne D. Walling

Motor fluctuations are a major complication for patients with Parkinson's disease during treatment with levodopa (Larodopa). Adjuvant medications such as pergolide (Permax) or entacapone (Comtan) can provide partial improvement but may require complex schedules and careful dosage titration. Rascol and colleagues studied a new selective, irreversible, second-generation monoamine oxidase inhibitor, rasagiline mesylate (Agilect), as an adjuvant medication to levodopa in patients with Parkinson's disease.

The authors conducted an 18-week, randomized, double-blind, parallel group trial of rasagiline against a placebo and entacapone. More than 600 patients with confirmed, stable Parkinson's disease were recruited from 74 centers. Participants were receiving optimal levodopa therapy and were able to maintain 24-hour symptom diaries. Patients with Mini-Mental State Examination scores of 24 or less were excluded from the study, as were those with concomitant psychiatric conditions. Following a two- to four-week run-in phase, participants were randomly assigned to receive adjunctive therapy with rasagiline (1 mg daily), entacapone (200 mg with each dose of levodopa), or placebo. Dummy pills were used to ensure that each patient took a similar number of pills daily regardless of treatment group. Physicians could adjust the levodopa dose during the first six weeks of the treatment phase if dyskinesia became problematic. During the final 12 weeks of the study, the dose of levodopa remained constant. The primary outcome was the total daily "off-time" of absent or poor motor function as recorded by patients in diaries. Patients were instructed to record "on-time" (with or without dyskinesia), off-time, or sleep every 30 minutes in their diaries for the three consecutive days before clinic visits. Secondary measures included clinical global improvement during on-time, ability to complete activities of daily living during off-time, and subscores of the Unified Parkinson's Disease Rating Scale (UPDRS). Patients were assessed at weeks 6, 10, 14, and 18 after baseline for these measures, plus monitoring for adverse events, physical and neurologic examination, electrocardiography, and any change in medical information.

The 231 patients assigned to rasagiline were comparable in all significant variables to the 227 assigned to entacapone and the 229 assigned to placebo adjuvant therapy. The mean age was 64 years, and the mean duration of Parkinson's disease was nine years. The average participant had taken levodopa for 7.5 years, and the average daily dose was around 700 mg. At the beginning of the study, patients reported about 5.5 hours of off-time daily plus about 1.4 hours of on-time with troublesome dyskinesia. Results were reported for 222 patients in the rasagiline group, 218 in the entacapone group, and 218 assigned to placebo. The average daily off-time was significantly reduced from baseline in the rasagiline and entacapone groups. Reductions of more than one hour daily were evident by the six-week assessment and were more than triple the improvement in the placebo group. Patients in the active treatment groups recorded a corresponding increase in daily on-time, mostly without dyskinesia. The improvements in the diaries were verified by verbal reports from patients and caregivers, plus a small but significant dose reduction in levodopa was seen in these groups. By week 18, the clinical global improvement score had improved significantly for rasagiline (0.49 units) and entacapone (0.36 units) compared with placebo. Symptom scores for tremor, rigidity, and bradykinesia, scores for activities of daily living, and motor function during on-time also improved significantly in both active treatment groups compared with placebo. Rasagiline had a similar effect to entacapone in most measures. The exceptions were subscores of the UPDRS relating to postural instability and gait disturbance, freezing, and motor function. These subscores were significantly improved by rasagiline but not by entacapone.

Adverse effects were common and occurred equally in all three groups. The most common adverse effect was postural hypotension. Most adverse effects were not serious, but 41 patients experienced serious adverse effects (12 each in the rasagiline and entacapone groups and 17 in the placebo group). Discontinuation was attributed to adverse events by seven patients taking rasagiline, 16 taking entacapone, and 11 in the placebo group.

The authors conclude that a daily dose of 1 mg rasagiline as adjunctive therapy reduced off-time and improved motor symptoms in patients taking maximal doses of levodopa for Parkinson's disease. The effects were similar to entacapone but were marginally better and associated with fewer adverse effects. A major advantage of rasagiline is its convenient dosing and the avoidance of dose titration.

ANNE D. WALLING, M.D.

Rascol O, et al. Rasagiline as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet March 12, 2005;365:947-54.

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