Levodopa

Levodopa therapy - still the cornerstone for the treatment of Parkinson's Disease

Levodopa is a principal medical treatment for the symptoms of Parkinson's Disease. It successfully provides relief from the main symptoms of the condition and dramatically enhances the life of people with Parkinson's Disease by improving motor function, mobility and enabling participation in everyday activities.

How Levodopa therapy works

The human body is made up of millions of cells. Cells of the nervous system are called neurons and their role is to receive and send information from one area of the body to another. Parkinson's Disease is caused by the loss of neurons that produce a substance called dopamine in the brain. Dopamine is an important neurotransmitter or chemical messenger in the nervous system. The loss of these dopamine-containing cells affects the body's ability to regulate and control normal movements, resulting in the symptoms of Parkinson's Disease.

As dopamine does not cross the blood-brain barrier, it cannot be used directly as a treatment for Parkinson's Disease. However, Levodopa (also commonly referred to as L-dopa) which is a chemical cousin of dopamine, does gain access to the brain where it is converted to dopamine to replace the brain's dwindling supply. This increase in dopamine levels enables normal body movements to be restored and reduces the symptoms of Parkinson's Disease

The development of Levodopa

Levodopa was the first breakthrough in the treatment of Parkinson's Disease. Its development was based on the discovery that people with Parkinson's Disease experience a severe loss of a substance in the brain - a chemical messenger - called dopamine. Since its introduction in the late 1960's, when it was heralded as a 'miracle' medication, Levodopa has remained the cornerstone of Parkinson's Disease therapy. More than 30 years after its discovery, Levodopa is still the most widely used treatment for Parkinson's Disease, and almost all patients require Levodopa at some point during the course of their illness.

During the first few years of Levodopa clinical use, large amounts of Levodopa were needed to be effective. These large doses were associated with side-effects such as nausea and vomiting and were due to the rapid breakdown of Levodopa in the body by enzymes. One of the main enzymes involved in this breakdown of Levodopa is peripheral dopa-decarboxylase (DDC). It was quickly realised that by inhibiting this enzyme using a DDC inhibitor, it was possible to reduce the Levodopa dose by 70%, thereby reducing the severity of side-effects. This combination is so effective that, today, Levodopa is almost always given in the same tablet with a DDC inhibitor, either carbidopa or benserazide. However, when DDC is inhibited another enzyme, catechol-O-methyl transferase (COMT), takes over the breakdown of Levodopa. Consequently, COMT inhibitors were recently developed as a way of further improving the delivery of Levodopa to the brain.

Levodopa enters the brain, where it is converted to dopamine to replace the brain's dwindling supply. By inhibiting the breakdown of Levodopa in the body, DDC and COMT inhibitors increase the amount of Levodopa that enters the brain.

The benefits of Levodopa therapy

Levodopa's success in treating the major symptoms of Parkinson's Disease is a triumph of modern medicine. Levodopa therapy controls the main symptoms of Parkinson's Disease and allows the majority of patients - who would otherwise become very disabled - to lead relatively normal and active lives. Levodopa therapy dramatically reduces rigidity (muscle stiffness), tremor (shaking), bradykinesia (slowness of movement), gait (impaired walking), hypomimia (reduced facial expression) and micrographia (small, cramped handwriting). Levodopa therapy also improves alertness, speech, swallowing, quality of sleep, memory loss, depression, excess salivation and seborrhea (oily, crusty, scaly skin). As result, many patients have reported significant improvements in quality of life and an overall sense of well-being following treatment with Levodopa.

The question of toxicity and Levodopa

Questions have been raised concerning the possible damaging effect of Levodopa on the dopamine cells of the brain, which could result in acceleration/worsening of Parkinson's Disease. This was based on experiments that showed that the addition of Levodopa to these specific cells caused them to die. The cells, however, were cultured, meaning that they were artificially grown in a laboratory rather than in their natural environment. This is significant, because when the laboratory conditions were changed to more closely resemble that of the normal functioning human brain, the dopamine cells did not die, and some studies instead showed that the cells actually grew better when Levodopa was added. More importantly, studies in humans have failed to demonstrate any damaging effects of Levodopa on the dopamine cells of the brain, and experts agree that there is no convincing evidence that Levodopa is damaging to the brain.

The effects of long-term therapy with Levodopa

Although Levodopa is very effective at improving mobility and motor function early on, long-term treatment with Levodopa can be associated with various complications. Some patients may develop abnormal involuntary movements such as twitching, nodding and jerking which are known as 'dyskinesias'. These dyskinetic movements are most often associated with Levodopa peak effects within the brain, i.e. about 30-60 minutes after a dose. Other patients may find that their Parkinson's symptoms begin to re-emerge or become noticeably worse before it is time to take their next dose of Levodopa. This is known as the 'wearing-off' phenomenon and may give rise to periods of time when certain symptoms such as tremor, rigidity and bradykinesia can no longer be effectively controlled. However, these complications can usually be overcome by adjusting the dosage, timing or frequency of Levodopa, or by adding a different treatment. Patients may also be prescribed a COMT inhibitor, such as entacapone, with their existing Levodopa medication. COMT inhibitors improve the availability of Levodopa in the body and extend the duration of action of each Levodopa dose, thereby increasing the amount of time when the symptoms of Parkinson's are well controlled. It is also now possible to switch from traditional Levodopa formulations to Stalevo®, a new Levodopa formulation that includes Levodopa, carbidopa and entacapone in one pill. In addition, dopamine agonists, which mimic the action of natural dopamine, can also be prescribed as an 'adjunct' to Levodopa therapy. Other commonly used antiparkinsonian drugs include anticholinergic drugs which are mainly helpful for tremor, the drug amantadine which may provide mild symptomatic benefit and is useful for the treatment of dyskinesias and the MAO-B inhibitor selegiline, which can be given in combination with Levodopa, to reduce the breakdown of dopamine and amplify the effects of Levodopa.

Levodopa is available in many different formulations to suit individual patient needs

There are currently three formulations of Levodopa available in Europe: Madopar® (Levodopa combined with benserazide), Sinemet® (Levodopa combined with carbidopa) and recently Stalevo® (Levodopa combined with both carbidopa and entacapone). They are all available in several different strengths and doses as tablets. Madopar® and Sinemet® are also available as controlled release preparations, which can be useful as night-time preparations as they have a longer duration of action. Levodopa is generally administered by mouth and is usually taken several times a day.

In more complicated situations, Levodopa can also be given by continuous infusion either intravenously (a slow injection of Levodopa into a vein) or via a computer-controlled pump placed in the small intestine. Levodopa can also be given as a liquid formulation, which can help control severe motor fluctuations.