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

Mov Disord. 1990;5(4):298-303. doi: 10.1002/mds.870050407.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activities of Daily Living
  • Antiparkinson Agents*
  • Brain / drug effects*
  • Carbidopa / administration & dosage
  • Carbidopa / adverse effects
  • Delayed-Action Preparations
  • Dopamine Agents*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Combinations
  • Humans
  • Levodopa / administration & dosage
  • Levodopa / adverse effects
  • Oxazines / administration & dosage*
  • Oxazines / adverse effects
  • Parkinson Disease / drug therapy*
  • Receptors, Dopamine / drug effects*
  • Receptors, Dopamine D2


  • Antiparkinson Agents
  • Delayed-Action Preparations
  • Dopamine Agents
  • Drug Combinations
  • Oxazines
  • Receptors, Dopamine
  • Receptors, Dopamine D2
  • carbidopa, levodopa drug combination
  • naxagolide
  • Levodopa
  • Carbidopa