Continuous dopaminergic stimulation reduces risk of motor complications in parkinsonian primates

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Abstract

Levodopa or short-acting dopamine (DA) agonist treatment of advanced parkinsonian patients exposes striatal DA receptors to non-physiologic intermittent stimulation that contributes to the development of dyskinesias and other motor complications. To determine whether continuous dopaminergic stimulation can delay or prevent onset of motor complications, four MPTP-lesioned, levodopa-naive cynomolgus monkeys were implanted subcutaneously with apomorphine containing ethylene vinyl acetate rods. Three other MPTP-lesioned monkeys received daily injections of apomorphine. Animals receiving apomorphine rods showed improved motor function (‘ON’ state) within 1 day of implantation, and remained continually ‘ON’ for the duration of treatment (up to 6 months) without developing dyskinesias. Injected animals also showed similar improvement in motor function after each apomorphine injection. However, these primates remained ‘ON’ for only 90 min and within 7–10 days all developed severe dyskinesias. Implanted monkeys evidenced local irritation, which was alleviated by steroid co-therapy.

Introduction

Alterations in the motor response to standard dopaminergic therapy constitute a major source of disability in patients with later stage Parkinson's disease (PD) ( Ahlskog and Muenter, 2001, Martignoni et al., 2003, Miyawaki et al., 1997). Increasing evidence suggests that the intermittent stimulation of striatal dopamine (DA) receptors contributes to the pathogenesis of these progressive complications ( Bezard et al., 2001, Chase, 2004, Chase and Oh, 2000a, Chase and Oh, 2000b, Olanow et al., 2000). In parkinsonian rats, 3 weeks of twice-daily levodopa alters motor responses in ways that mimic human motor fluctuations; these responses do not occur if levodopa is administered by round-the-clock infusion ( Juncos et al., 1989, Papa et al., 1994). In parkinsonian monkeys, dyskinesias begin within 1–2 weeks of daily dopaminomimetic therapy ( Smith et al., 2003 ), but do not appear when treated via continuous infusion for 27 days ( Morissette et al., 1997 ). Dyskinesias develop sooner in parkinsonian primates given levodopa (90 min half-life) than in those treated with DA agonists (with half-lives exceeding 4 h) that provide relatively more constant dopaminergic stimulation ( Jenner, 2000 ). Similarly, motor complications tend to subside in PD patients when intermittent dopaminergic therapy is replaced by more continuous modes of administration ( Baronti et al., 1992, Hadj Tahar et al., 2000, Mouradian et al., 1990). These observations suggest that the risk of motor response complications may be reduced by therapeutic regimens that provide steady and thus more physiologic DA replacement for this normally tonically operating system ( Chase et al., 1989, Skirboll et al., 1990).

The only currently available means to constantly administer dopaminergic agents, by continuous infusion has limited practicality. Recently, an ethylene vinyl acetate (EVA) copolymer system has been developed that enables the continuous release of drugs at therapeutic levels over extended periods ( Lesser et al., 1996, White, 2003). When loaded with apomorphine ( Raasch et al., 2000 ), a highly effective DA agonist for the relief of parkinsonian symptoms ( Bravi et al., 1994, Manson et al., 2002, Poewe and Wenning, 2000, Wenning et al., 1999), these implants have performed safely and reliably upon subcutaneous placement in pigs (IDB, Titan Pharmaceuticals). Here, we evaluated the hypothesis that the long-term continuous administration of apomorphine will maintain antiparkinsonian efficacy but not induce dyskinesias in previously untreated MPTP lesioned primates. In addition, the safety and tolerability of these apomorphine-containing EVA rods administered by themselves and with steroid co-therapy was assessed in this primate PD model.

Section snippets

Animals

Studies were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals in 7 adult male cynomolgus (Macaca fascicularis) primates weighing 6.5–7.3 kg. All were housed individually, under stable room conditions, with a 12-h light/dark cycle. Each received a standard biscuit diet twice daily supplemented with fruit and had free access to water. All primates were rendered parkinsonian by the subcutaneous administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Results

All MPTP-lesioned monkeys given apomorphine by subcutaneously implanted rods showed essentially total remission of parkinsonian signs (fully ‘ON’) within 6–12 h after implantation, and continued to evidence stable motor benefit until explantation after 11 (first animal), 22 (second animal) and 24 weeks (third and fourth animal) with no fluctuations in response (constant Disability Scale scores of 0–1). Animals treated once daily by apomorphine injection (2.0 mg/kg) also turned fully ‘ON’

Discussion

Results from this study indicate that subcutaneous implanted EVA rods can stably release apomorphine for up to 6 months, allowing continuous ‘ON’ time in MPTP-lesioned primates without the appearance of dyskinesias. Apomorphine injections produced equivalent, although transient improvement in parkinsonian signs, but lead to the development of dyskinesias within 7–10 days. Plasma apomorphine concentrations required for optimal motor improvement in the injected animals were an order of magnitude

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