Most new drugs aim to supplement L-dopa, generally to make its effects last longer. L-dopa, also known as levodopa, is the biological precursor to dopamine. Dopamine itself cannot be used, because it cannot cross the blood-brain barrier. L-dopa's chemical structure is such that it can go from the bloodstream to the brain easily, and, once there, is converted to dopamine. L-dopa is typically given in combination with a dopa decarboxylase inhibitor, in order to prevent the body from changing it into chemicals other than dopamine. This combination of L-dopa and inhibitor is sold under the trade name Sinemet.
Typically, L-dopa is initially effective in reducing Parkinson's symptoms, and it extends the life of the average Parkinson's patient by five years (Mack 1996). However, it does not treat the underlying problem of cell death. It is not surprising that higher doses become necessary to maintain the same relief. Other problems arise when the brain develops a tolerance to increased dopamine levels. In response, dopaminergic cells eventually decrease their production, and the cells of the globus pallidus decrease the number of dopamine receptors present. Both of these changes make it more difficult to control motor movements. Tics, spasms, and muscle clenching may appear, in addition to the usual Parkinsonian tremors and bradykinesia (unusually slow movements). This is termed Dopa-Induced Diskinesia (DID) and is an almost inevitable result of chronic L-dopa treatment (Hershey et al 1998).
In general, DID first manifests inself just as one dose of L-dopa wears off, before the next takes effect. This leads to a see-saw balance between "on" and "off" states (between normal movement and DID). The decrease of "off time" is a major goal of most new drugs. Other side effects of chronic L-dopa treatment include possible hallucinations, and even psychosis. These have been treated fairly successfully with clozapine, an anti-psychotic, which also tends to diminish Parkinsonian tremors(New England Journal of Medicine 1999).
Additionally, there has been some concern that L-Dopa treatment actually hastens the progression of the disease. Metabolism of dopamine creates free radicals, which have been linked both to cancer and to cell death. Essentially, by increasing the output of the dopaminergic cells, the drug may be working them to death. Whether this actually occurs is still a matter of debate. The extent to which dopa-induced cell death should be a concern has not been decided, but this possibility has been an impetus for developing alternative drugs.