Transdermal Administration of Piribedil Reverses MPTP-induced Motor Deficits in the Common Marmoset

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Abstract
The ability of transdermal administration of the dopamine D2/D3 agonist piribedil (1-[3,4-methylenedioxybenzyl)]-4-[(2-pyrimidinyl)]piperazine) to reverse hypokinesia and other motor deficits observed in MPTP-treated common marmosets was investigated. Piribedil (2.5-10.0 mg/animal), applied directly to the skin of the abdomen as a paste, produced a long-lasting and concentration-dependent reversal of motor deficits. The antiparkinsonian actions of piribedil occurred within 10 minutes of drug administration and lasted as long as 10 hours. Transdermally applied piribedil produced a pattern of locomotor activity characteristic of normal motor behavior in this species. Symptoms of nausea (marked excessive salivation, retching, and/or vomiting) were not observed after transdermal application of piribedil. Additionally, pretreatment with the peripheral dopamine antagonist domperidone enhanced the antiparkinsonian effects of piribedil. Application to the skin of monolayer or bilayer patches impregnated with piribedil also produced a marked increase in locomotor activity and reversal of motor deficits. After application of various patch fractions (whole, one-half, or one-fourth), the increase in locomotor activity and reversal of disability correlated well with the surface area of skin covered. Measurement of serum levels of piribedil after single application of bilayer patches showed a positive relationship between drug levels and antiparkinsonian activity. Repeated daily application of piribedil bilayer patches for 5 days to MPTP-treated common marmosets primed to show dyskinesia by previous exposure to L-Dopa produced antiparkinsonian activity accompanied by dyskinetic movements. Transdermal administration of dopamine agonists such as piribedil may provide a useful means of producing a long-lasting reversal of motor deficits in Parkinson's disease while avoiding acute adverse effects such as nausea.