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Sustained‐release (+)‐PHNO [MK‐458 (HPMC)] in the treatment of Parkinson's disease: Evidence for tolerance to a selective D 2 ‐receptor agonist administered as a long‐acting formulation
Author(s) -
Cedarbaum Jesse M.,
Clark Mary,
Toy Linda H.,
GreenParsons Alison
Publication year - 1990
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.870050407
Subject(s) - carbidopa , agonist , levodopa , dose , dopamine agonist , medicine , parkinson's disease , pharmacology , anesthesia , receptor , disease
4‐‐Propyl‐9‐hydroxynaphthoxazine, or MK‐458 (HPMC), a selective, nonergot D2 agonist administered orally twice a day in sustained‐release form, was studied as adjunctive therapy with carbidopa‐levodopa (Sinemet) in 12 Parkinson's disease patients with motor response fluctuations. The dosage of agonist was gradually increased over 12 weeks to a maximum tolerated level of up to 60 mg/day, and that of Sinemet was reduced concurrently. After 8 weeks, reduction of Sinemet averaged 45.1%, but over the next 4 weeks, despite a continued increase in dosage of the agonist, patients were unable to decrease their Sinemet further, and by 12 weeks mean reduction in Sinemet was only 32%. Only five patients completed the planned 24‐week study, mostly due to progressive loss of efficacy. The MK‐458 is capable of partially substituting for Sinemet in dosages employed in this study. Reduced sensitivity to the drug can appear over a relatively short time, perhaps as a result of downregulation of postsynaptic dopamine receptors.