THE EXPERIMENTAL EVALUATION OF ANTIPARKINSONIAN COMPOUNDS

For many years up to and including the present time, the major evaluation of agents useful in relieving the tremor and other symptoms of Parkinson’s syndrome has rested on the empirical testing in patients. As a final evaluation, this therapeutic test is, of course, indispensable, but the many limitations of this method have rendered more difficult the rational introduction of newer compounds. The use in these clinical studies of newer blind-testing techniques, placebo medication, and optimal routes of administration is made difficult by the necessity of retaining the patient’s cooperation. The objective measurement of symptoms is still in its infancy. Consequently, it has not generally been possible to obtain dose-response curves for drugs and to apply currently available statistical methods. Many recent improvements along these lines, however, can be noted. The isolated rabbit intestinal-strip preparation has attained widespread popularity as a means of testing compounds for peripheral cholinergic blocking activity. This bioassay procedure has recently become an important predictive measure, enabling a slightly more rational selection of compounds for therapeutic testing, but a wide gap still exists between the ability to measure the potency of an agent for peripheral blockade of the muscarinic effects of acetylcholine and the ability to select a drug capable of modifying the activity of the extrapyramidal motor nuclei. Although the role of damage to the extrapyramidal system as a causative factor in Parkinson’s disease has been known for some time, the evaluation of antiparkinsonian drugs in animals with hyperkinesia is of relatively recent origin. Several widely varying types of hyperkinesia in animal preparations have been used, including those acutely drug-induced, longer-lasting “biochemical lesions,” and surgically produced lesions of chronic persistence. Drawing upon older but incomplete knowledge of the actions of nicotine, Bovet and Longo’ attempted to correlate antagonistic effects of compounds to nicotine-induced tremor and convulsions in the rabbit with human antitremor activity. They tested atropine and found it lacking in protection, but a variety of agents, including several phenothiazines, showed evidences of nicotine antagonism. The interpretation of these data remains obscure, and the technique must be considered of doubtful predictive value until more is known concerning the site or sites of action of nicotine in the central nervous system. Early studies with diisopropyl fluorophosphate (DFP) described generalized