title: Sustained-release (+)-PHNO [MK-458 (HPMC)] in the treatment of Parkinson's disease: evidence for tolerance to a selective D2-receptor agonist administered as a long-acting formulation.
abstract: 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 down-regulation of postsynaptic dopamine receptors.
authors.affiliation: Department of Neurology and Neuroscience, Cornell University Medical College, White Plains, New York.
authors.forename: J M
authors.initials: JM
authors.lastname: Cedarbaum
authors.forename: M
authors.initials: M
authors.lastname: Clark
authors.forename: L H
authors.initials: LH
authors.lastname: Toy
authors.forename: A
authors.initials: A
authors.lastname: Green-Parsons
mesh_terms: D000203:Activities of Daily Living; D000978:Antiparkinson Agents; D001921:Brain / Q000187:drug effects*; D002230:Carbidopa / Q000008:administration & dosage / Q000009:adverse effects; D003692:Delayed-Action Preparations; D015259:Dopamine Agents; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects; D010078:Oxazines / Q000008:administration & dosage* / Q000009:adverse effects; D010300:Parkinson Disease / Q000188:drug therapy*; D011954:Receptors, Dopamine / Q000187:drug effects*; D017448:Receptors, Dopamine D2
chemical_list: D000978:Antiparkinson Agents; D003692:Delayed-Action Preparations; D015259:Dopamine Agents; D004338:Drug Combinations; D010078:Oxazines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; C009265:carbidopa, levodopa drug combination; C042631:naxagolide; D007980:Levodopa; D002230:Carbidopa