Oral r-(-)-11-o-valeryl-n-n-propylnoraporphine reverses motor deficits in mptp-treated marmosets
| Autor: | Peter Jenner, Anna W. Sromek, Andrew J. Lees, Louise Lincoln, Sarah Rose, Michael J. Jackson, John L. Neumeyer, Ria Fisher |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Parkinson's disease business.industry MPTP Pharmacology medicine.disease Dopamine agonist Effective dose (pharmacology) Apomorphine 03 medical and health sciences Subcutaneous injection chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Neurology chemistry Dyskinesia Oral administration medicine Neurology (clinical) medicine.symptom business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Movement Disorders. 31:1381-1388 |
| ISSN: | 0885-3185 |
| Popis: | Background The D1/D2 dopamine agonist apomorphine has poor oral bioavailability, necessitating subcutaneous administration in the treatment of Parkinson's disease (PD). Acute subcutaneous injection is used as rescue therapy from “off” periods, whereas continuous subcutaneous infusion is used to increase “on” periods and to reduce dyskinesia when oral treatment fails. An orally active derivative of apomorphine would avoid the need for parenteral administration. We now describe the effects of the orally active compound R-(-)-11-O-valeryl-N-n-propylnoraporphine (11-OH-NPa valerate) on reversal of motor disability and expression of dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated, l-dopa-primed dyskinetic common marmosets. Methods Locomotor activity, motor disability, and dyskinesia were assessed in MPTP-treated marmosets following the administration of apomorphine (0.075 mg/kg, subcutaneous and 0.28 to 1.12 mg/kg, oral) and 11-OH-NPa valerate (0.19, 0.38, and 0.75mg/kg, oral). Results Subcutaneous administration of apomorphine (0.075 mg/kg) produced a short-lasting reversal of motor disability and the expression of established dyskinesia, but when administered orally (0.28-1.12 mg/kg) it had no effect. In contrast, oral treatment with 11-OH-NPa valerate (0.19 and 0.75 mg/kg) induced a dose-related reversal of motor disability and increased locomotor activity with only mild to moderate dyskinesia. Only at the highest dose (0.75 mg/kg) was marked dyskinesia seen accompanying an extended period of motor disability reversal and increased locomotor activity. Conclusion Oral administration of 11-OH-NPa valerate produced a rapid reversal of motor disability and, at effective dose levels, had a limited propensity to induce dyskinesia. 11-OH-NPa valerate is the first orally active derivative of apomorphine with potential for use in PD. © 2016 International Parkinson and Movement Disorder Society |
| Databáze: | OpenAIRE |
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