Non-dopaminergic therapy in Parkinson's disease

Abstract

Parkinson's disease no longer seems to be a disease entity caused by only one pathogenetic factor. The facile characterization of Parkinson's disease as a more or less isolated disorder of the dopaminergic system proves to be an unacceptable oversimplification of the pathology of the disease. Characteristically, not all dopaminergic systems of the central nervous system are involved in the degenerative process. In addition to the nigrostriatal dopaminergic pathway, parts of the glutamatergic, cholinergic, tryptaminergic, noradrenergic, adrenergic, serotonergic, and peptidergic neurons show serious cytoskeletal damage. In the light of these findings, drugs influencing these transmitter systems should be useful in the treatment of parkinsonian symptoms. For this reason, non-dopaminergic drugs are gaining more and more importance. Besides the theoretically interesting adenosine A2 receptor antagonists, budipine, a polyvalent potent new antiparkinsonian drug, has been tested in clinical studies. Budipine is a potent non-dopaminergic antiparkinsonian drug with pharmacological effects that are not comparable to those of conventional drugs applied in Parkinsonian pharmacotherapy. Budipine experimentally increased the brain content of noradrenaline, dopamine, serotonin, and histamine. The dopamine, serotonin, noradrenaline, gamma aminobutyric acid (GABA), and endorphine receptor affinities were not altered, but N-methyl-D-aspartate (NMDA) and sigma receptor affinities were increased as shown by in vivo and in vitro trials with budipine. MPTP (N-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine) and MPP+ antagonistic effects have also been demonstrated. Budipine also shows neuroprotective as well as symptomatic antiparkinsonian effects. In two randomized, double-blind, multicenter, placebo-controlled studies, relevant therapeutic effects have been observed in previously untreated, so-called "de-novo" parkinsonian patients and in subjects in later stages of the disease. Budipine significantly reduces akinesia, rigidity, and tremor. Optimal effects of budipine can be seen 4-6 weeks after starting treatment with this substance. Budipine can be added to all available antiparkinsonian drugs. An open, prospective, long-term study of 2532 patients with Parkinson's disease (Study BY701/01A) confirmed the favorable safety and tolerability profiles of budipine.