Beans, roots and leaves: a brief history of the pharmacological therapy of parkinsonism.

It is not clear whether parkinsonism as it is now defined - a progressive neurodegenerative disorder of the basal ganglia characterized by sharply reduced striatal dopamine levels - has always affected a significant minority of aged persons, but suggestive evidence to this effect is reviewed. THe major discussion commences, however, with the administration of various plant alkaloids to parkinsonism patients in the second half of the 19th century. Antiparkinsonian therapy since this time can be divided into a number of phases: 1. Employment of alkaloids derived from solanaceous plants: initially hyoscyamine, then hyoscien/scopolamine. 2. With the outbreak of encephalitis lethargica during the First World War, parkinsonian patient numbers increased dramatically, leading to a multiplicity of new directions, including high dose atropine and harmala alkaloid therapies. 3. The "Bulgarian treatment", popularized in western Europe in the mid-1930s, was also a belladona alkaloid-based therapy, but associated with greater efficacy and few side effects. This approach, whether as actual plant extracts or as defined combinations of belladona alkaloids, remained internationally dominant until the end of the 1940s. 4. Following the Second World War, synthetic antiparkinsonism agents were developed with the aim of overcoming the deficiencies of belladonna alkaloid therapy. These agents fell into two major classes: synthetic anticholinergic agents, such as benzhexol, and antihistaminergic drugs, including diphenhydramine. 5. A complete change in direction was heralded by the discovery in 1960 of the striatal dopamine deficit in parkinsonism. This led to the introduction of L-DOPA therapy, the first approach directed against an identified physiological abnormality in the disorder. 6. Subsequent developments have thus far refined of supplemented the L-DOPA effect. Recent attempts to develop neuroprotective or -restorative approaches are also briefly discussed. The history of antiparkinsonian therapy illustrates the fact that the nature of experimental clinical pharmacology has markedly changed during the 20th century: No longer the preserve of individual physicians, it is now based firmly on fundamental laboratory research, the clinical relevance of which is not always immediately apparent, and which is only later examined in clinical trials. It is nonetheless concluded that antiparkinsonian therapy was never 'irrational', but has always been necessarily rooted in current knowledge regarding neural and muscular function. The achievements of L-DOPA therapy, the first successful pharmacological treatment for a neurodegenerative disorder, derived from the fruitful union of hte skills and contributions of different types by laboratory scientists, pharmacologists and clinicians.