Investigational drugs

Handbook of Clinical Neurology, Vol. 84 (3rd series) Parkinson’s disease and related disorders, Part II W. C. Koller, E. Melamed, Editors # 2007 Elsevier B. V. All rights reserved

Chapter 37

Investigational drugs CARLO COLOSIMO* AND GIOVANNI FABBRINI Dipartimento di Scienze Neurologiche, Universita` La Sapienza, Rome, Italy

37.1. Introduction The introduction of the dopamine precursor levodopa (LD) as the mainstay of treatment of Parkinson’s disease (PD) has provided excellent symptomatic benefit for the majority of patients. However, the effects of dopaminergic therapy are limited by the fact that LD has not been shown to slow the progression of the disease and that PD patients still face major shortcomings in the chronic phase of the disease. Fluctuations and levodopa-induced dyskinesia (LID) are the major complications in the current therapeutic approach to the treatment of PD, deeply affecting patients’ quality of life. More than 50% of all patients treated with LD for 5 years or more develop motor response fluctuations, which are usually associated with the appearance of LID (Nutt and Holford, 1996; Colosimo and De Michele, 1999; Brotchie, 2000). The exact pathophysiology of fluctuations and LID is not fully understood, but they are probably related to striatal dopamine receptor changes following dopaminergic denervation and chronic exposure to LD (Crossman, 1990). These receptor alterations include changes of sensitivity, relative balance between different dopamine receptor subtypes and different translational and neuromodulatory-system responses (Crossman, 1990; Colosimo et al., 1996; Brotchie, 2000; Bezard et al., 2001). Duration of the disease and early initiation of LD therapy are key factors for the development of motor complications, though the poor pharmacokinetics of LD (very short half-life, inconsistent absorption) also plays an important role. As a result, the dopamine agonists, compounds with a better pharmacokinetic profile than LD, were developed. Based on experimental data showing that de novo administration of dopamine agonists to non-human primates rendered parkinsonian

with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced less dyskinesia than LD (Bedard et al., 1992; Pearce et al., 1998), several clinical studies have been conducted, all showing that dopamine agonists can alleviate parkinsonian symptoms in previously untreated patients with a much reduced incidence of fluctuations and dyskinesia (Rascol et al., 2000; Parkinson Study Group, 2004b). Unfortunately, this strategy has its limitations since only approximately 30% of parkinsonian patients show a good and durable response to dopamine agonists as monotherapy. Chronic use of dopamine agonists is also associated with frequent psychiatric side-effects, including visual hallucinations, delusions and paranoid psychosis. Furthermore, dopamine agonists more easily elicit dyskinesia when administered together with LD or following ‘priming’ with LD. Therefore, in the foreseeable future, dopamine replacement in the form of LD is likely to remain the mainstay of therapeutic approaches for PD. Attempts to reduce dyskinesia by means of drug holidays, controlled-release LD preparations, long-acting dopamine agonists (cabergoline), or other adjunct therapies such as monoamine oxidase-B (MAO-B) or catechol-O-methyl-transferase inhibitors, have generally met with limited success in the clinic (Colosimo and De Michele, 1999). Continuous wakingday subcutaneous apomorphine infusion is effective in the long term, though not easily applicable to the majority of patients (Colosimo et al., 1994). As a result, several new treatment strategies for PD are currently being investigated, particularly those targeting non-dopaminergic pathways. Furthermore, in PD there is still no satisfactory approach to the treatment of cognitive disturbances and dementia (Brown and Marsden, 1990), autonomic dysfunction (Senard et al., 2001), balance, walking

*Correspondence to: Carlo Colosimo, Dipartimento di Scienze Neurologiche, Universita` La Sapienza, Viale dell’Universita` 30, I-00185 Rome, Italy, E-mail: [email protected], Tel: þ39-06-4991-4511, Fax: þ39-06-4991-4700.

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difficulties and the risk of falling (Bloem et al., 2004), speech disorders (Pinto et al., 2004), psychiatric and behavioral symptoms (Wint et al., 2004) and sleep problems (Brotini and Gigli, 2004). Based on all the previous observations, therapeutic research in the future is expected to be moving in several different directions. Among these are: (1) development of socalled neuroprotective drugs, capable of blocking or at least slowing down the degenerative process responsible for neuron death, or even of restorative strategies, which would allow to normal brain function to be regained; (2) further improvement in the replacement of dopaminergic loss; (3) antidyskinetic drugs; and (4) symptomatic drugs acting on neurotransmitters other than dopamine, or which may target the brain in other areas rather than only in the striatum.

37.2. Neuroprotective therapies Interventions that can slow or halt the progression of PD remain a crucial unmet need. Several promising approaches are under development for the potential of neuroprotection in PD. However, the confounding fact of the possible symptomatic effects of the drugs tested, the placebo effect, the choice of optimal endpoint and the need for validated surrogate markers are all significant issues when studying a putative neuroprotective intervention in PD, which have not been completely addressed until now. Neuroprotection strate-

gies will derive directly from studies directed to an understanding of the pathogenesis and mechanisms of cell death. Current information suggests that neurodegeneration in PD is associated with a cascade of events that includes oxidant stress, mitochondrial abnormalities, failure in the ubiquitin-proteasome system to clear unwanted proteins, excitotoxicity, inflammation and possible other still not identified mechanisms (Dawson and Dawson, 2003). Considerable evidence suggests that cell death in PD, regardless of cause, occurs by way of signal-mediated apoptosis (Hirsch et al., 1999). Development of new drugs for neuroprotection is very fast. In a recent survey of potential neuroprotective agents for clinical trials in PD (Ravina et al., 2003), several compounds have been identified as potential effective neuroprotective agents, but only a few are real candidates for phase II or III studies. The development status of these compounds is summarized in Table 37.1. 37.2.1. Monoamine oxidase inhibitors 37.2.1.1. Rasagiline Rasagiline is a propargylamine and is a potent, irreversible, selective inhibitor of MAO-B with no amphetaminelike metabolites and with the capability of increasing DA release. Beside its activity on MAO enzymes, the neuroprotective properties of rasagiline may be linked to other factors, such as the capability of inhibiting apoptosis at three levels: (1) intranuclear translocation of

Table 37.1 Development status of neuroprotective/neurorestorative agents Compound

Company/institution

Class of compound

Phase of development

CEP-1347

Cephalon/H Lundbeck Kyowa Hakko Kogyo Spectrum Pharmaceuticals Vertex Pharmaceuticals Schering Amgen Guildford Pharmaceuticals Panacea Pharmaceuticals

Mixed-lineage kinase inhibitor

Withdrawn

Nerve growth factor agonist Neuroimmunophilin ligand

Phase II

Withdrawn Phase II Preclinical

Phytopharm plc/Yamanouchi Pharmaceutical Novartis Mitokor Curis/Wyeth Pharmaceuticals

Growth factor agonist Neuroimmunophilin-ligand a-Synuclein oligomerization inhibitors Dopamine modulator GAPDH inhibitor Estrogen analog Hedgehog agonist

Withdrawn Phase I Preclinical

ONO Pharmaceutical Eisai

Astrocyte modulator AMPA antagonist

Phase II Phase II

Leteprinim V-10367 Liatermine GPI-1485 PAN-408 PYM-50028 TCH-346 MITO-4509 Sonic hedgehog protein agonist ONO-2506 E-2007

Phase II

Adapted with permission from The Thomson Corporation and Johnston and Brotchie (2004). # 2004 The Thomson Corporation. GAPDH, glyceraldehyde-3-phosphate dehydrogenase; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid.

INVESTIGATIONAL DRUGS the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase; (2) induction of bcl-2; and (3) activation of mitochondrial permeability transition. Clinical studies on rasagiline have also confirmed the potential usefulness of this drug in the symptomatic treatment of PD. In early patients (TEMPO study) rasagiline was superior to placebo in improving Unified Parkinson’s Disease Rating Scale (UPDRS) motor and activities of daily living scores. More patients in the placebo group (16.7%) than those in rasagiline treatment (11.2%) needed LD within 12 months of the beginning of the study, although this difference was not significant. This study also included an initial 6-month placebo phase (delayed treatment) which showed that patients treated for 6 months with placebo and then allowed to receive the active drug did not catch up with those patients who were in active treatment since the beginning of the study. These data, although preliminary, suggest a disease-modifying effect rather than symptomatic benefit only (Parkinson Study Group, 2002, 2004a). 37.2.1.2. Zydis selegiline The usefulness of conventional selegiline is confounded by low bioavailability, extensive first-pass metabolism and production of amphetamine metabolites. Zydis selegiline (a rapidly disintegrating tablet) dissolves in the mouth on contact with saliva and undergoes pregastric absorption, providing high plasma levels of selegiline, almost completely avoiding first-pass metabolism and markedly reducing the production of amphetamine metabolites (Seager, 1998). Few studies have shown the potential usefulness of the drug in the treatment of advanced patients with motor fluctuations, increasing the time spent in the on phase. Side-effects more commonly reported were dizziness, dyskinesia, hallucinations, headache and dyspepsia, usually in the first 6 weeks of treatment (Waters et al., 2004). The possible role of zydis selegiline as a neuroprotective agent has not been tested. 37.2.2. Modulators of mitochondrial function Coenzyme Q1 is a ‘health supplement’ which is able to increase the activity of mitochondrial complex I activity and may act as an antioxidant. Preliminary evidence suggests that doses of 1200 mg/day, which are well tolerated, may slow functional decline as measured by UPDRS scores (Shults et al., 2002). Creatine is also a nutritional supplement which is converted to phosphocreatine, a metabolite functioning as an energy buffer able to transfer a phosphoryl group to adenosine diphosphate. Creatine has been shown to be protective in MPTP rodent models (Matthews et al.,

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1999). A pilot study using creatine and minocycline is under way. 37.2.3. Other mechanisms 37.2.3.1. Estrogens Epidemiological data suggest a reduced incidence of PD in women (Currie et al., 2004) and there are also several animal models in which estrogens appear as promising neuroprotective agents. The mechanism may involve neurotrophic effects as well as antioxidant effects (Dluzen and Horstink, 2003). 37.2.3.2. GM1 ganglioside GM1 ganglioside is a component of neuronal membranes, may facilitate the neurotrophic actions of brain-derived nerve growth factor (BDNF) and glialderived neurotrophic factor (GDNF), may inhibit apoptosis and may protect against excitotoxicity. Some preliminary data in PD have shown that the compound is well tolerated and has short-term symptomatic benefit (Schneider, 1998). However concerns still exist about its immunogenicity and the relationship with Guillain–Barre´ syndrome. 37.2.3.3. Neuroimmunophilin Neuroimmunophilin ligands (NILs) are drugs derived from the immunosuppressant FK506 (tacrolimus) that have been shown to have variable efficacy in reversing neuronal degeneration and preventing cell death (Gold and Nutt, 2002). In animal models mimicking PD they induce resprouting and are neurotrophic. Some evidence suggests that NILs may act through regulation of steroid hormone receptors. Other evidence suggests that NILs may protect neurons by upregulating the antioxidant glutathione and stimulating nerve regrowth by inducing the production of neurotrophic factors. Initial clinical trials have had mixed success. In one, patients with moderately severe PD showed no overall improvement in fine motor skills following 6 months of treatment with the neuroimmunophilin GPI 1485, although there was a decreased loss of dopaminergic nerve terminals or eventually an increase in dopaminergic terminals within 6 months of the higher dose of GPI 1485 drug treatment (Poulter et al., 2004). 37.2.3.4. Inhibitors of microglial inflammation (antiapoptotic kinase inhibitors) The c-Jun NH2-terminal kinase (JNK) signaling pathway is frequently induced by cellular stress and correlated with neuronal death. JNK signaling is therefore a promising target in PD for developing pharmacological intervention. CEP-1347 blocks the activation of

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the c-Jun/JNK apoptotic pathway in neurons exposed to various stressors and attenuates neurodegeneration in animal models of PD, eventually associated with microglial activation. CEP-1347 reduced cytokine production in primary cultures of human and murine microglia and in monocyte/macrophage-derived cell lines, stimulated with various endotoxins or the plaque-forming peptide Abeta1–40. Moreover, CEP-1347 inhibited brain tumor necrosis factor (TNF) production induced by intracerebroventricular injection of lipopolysaccharide in mice. As expected from a mixed linear inhibitor (MLK), CEP-1347 acted upstream of p38 and c-Jun activation in microglia by dampening the activity of both pathways (Lund et al., 2005). These data infer that MLKs may be important, yet unrecognized, modulators of microglial inflammation and demonstrate a novel anti-inflammatory potential of CEP-1347 (Johnston and Brotchie, 2004). The safety and tolerability of CEP-1347 have recently been studied in 30 patients with PD. Overall the drug was well tolerated and had no acute effect on parkinsonian symptoms or LD pharmacokinetics (Parkinson Study Group, 2004c). 37.2.3.5. Minocycline Minocycline is a semisynthetic, second-generation tetracycline derivative which crosses the blood–brain barrier and may inhibit microglial-related inflammatory events and also the apoptotic cascade. Several studies have shown that minocycline is neuroprotective in animal models of central nervous system trauma and neurodegenerative diseases; in particular, this compound has greatly enhanced survival in nigrostriatal dopaminergic neurons in the MPTP model of PD (Du et al., 2001). Minocycline has, therefore, been incorporated into an ongoing clinical investigation in untreated PD patients (Ravina et al., 2003).

37.3. Improvement of dopaminergic drugs Several strategies have been proposed and developed in order to improve the pharmacokinetics and pharmacodynamics of dopaminergic agents used in PD. The development status of all these compounds is summarized in Table 37.2. 37.3.1. Improvement of levodopa bioavailability Absorption of LD is very sensitive and depends on the state of the stomach and gastrointestinal system. Therefore efforts are under way to improve LD absorption. Recent attempts have shown that methylester LD (melevodopa) is effective as standard LD and may have the additional advantage of a faster absorption (Johnston and Brotchie, 2004).

Another approach is currently under investigation through the intraduodenal infusion delivery of LD. Advanced parkinsonian patients may benefit from this form of treatment in order to achieve more stable plasma LD levels (Nyholm et al., 2005). 37.3.2. Increase in the synaptic availability of dopamine Dopamine reuptake blockers, by enhancing and stabilizing intrasynaptic transmitter levels, could help palliate motor dysfunction in PD, in both early and advanced disease. In experimental animals with severe neurotoxin-induced dopaminergic neuron loss mimicking conditions in advanced PD, LD treatment after an effective pharmacologic dopamine transporter (DAT) blockade produces far higher elevations in extracellular DA than normally occur (Pearce et al., 2002). Thus, DAT inhibitors should act clinically to potentiate the antiparkinsonian action of LD. Moreover, because a reduction in DA reuptake prolongs its striatal half-life, motor fluctuations as well as dyskinesia and other adverse consequences of the intermittent stimulation of striatal DA receptors might diminish in the long term (Nutt and Holford, 1996). A randomized, double-blind, placebo-controlled study compared the acute effects of the monoamine uptake inhibitor NS 2330 with those of placebo in 9 fluctuating parkinsonian patients (Bara-Jimenez et al., 2004). Individuals randomly assigned to NS 2330 treatment were given an initial 1-week placebo run-in, followed by a treatment phase consisting of eight doses of 1.5 mg each, administered three times weekly. The cumulative total dose of 12 mg was selected to achieve plasma drug concentrations in therapeutic range, based on preliminary pharmacokinetic data obtained by the drug manufacturer. Remaining patients received placebo throughout the entire study. At the dose administered, no change in parkinsonian scores was found when NS 2330 was given alone or with LD. Moreover, NS 2330 coadministration did not appear to reduce the severity of dyskinesia or the duration of the antiparkinsonian response to LD. Since, under the conditions of this study, results failed to support the usefulness of dopamine reuptake inhibition in the treatment of advanced PD, this compound was withdrawn from clinical trials. 37.3.3. Dopamine agonists There is still work to be done to understand better the effects of selective D1 dopamine agonists in PD (Rascol et al., 1999, 2001a). It is realistic to hope for further innovations through the development of new

INVESTIGATIONAL DRUGS

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Table 37.2 Development status of symptomatic antiparkinsonian agents

Compound

Company/Institution

Class of compound

Dopaminergic Melevodopa

Chiesi Farmaceutici

SR-57667

Sanofi-Synthelabo

Safinamide

Newron Pharmaceuticals

Rasagiline

SLV-308

Teva Pharmaceutical Industries/H Lundbeck/Eisai NeuroSearch/ Boehringer Ingelheim Shire Pharmaceutical Group Pfizer Schwarz Pharma/Otsuka Pharmaceutical Solvay

Methyl-l-dopa/ carbidopa Irreversible MAO-B inhibitor? MAO-B inhibitor Naþ/Caþ channel blocker Irreversible MAO-B inhibitor

Talipexole

Boehringer Ingelheim

DU-127090

Solvay/H Lundbeck/Wyeth Pharmaceuticals BIAL Group

NS-2330 SPD-473 Sumanirole Rotigotine

BIA-3–202 Non-dopaminergic Istradefylline KF-17837 VR-2006 Donepezil

Kyowa Hakko Kogyo Kyowa Hakko Kogyo Vernalis Group Eisai/Pfizer/Wyeth-Ayerst International

Monoamine reuptake inhibitor Monoamine reuptake inhibitor D2-agonist D2-agonist

Phase of development

Other potential actions

Launched

–

Phase IIb

Neuroprotective

Phase III

Neuroprotective

Launched

Neuroprotective

Withdrawn

Withdrawn Launched

Cognitive enhancement Antidepressant Cognitive enhancement Antidepressant – –

Phase II

Antidepressant

Launched

–

Phase II

D2 partial agonist/ 5-HT1A agonist D2-agonist/a2adrenoceptor agonist D2 partial agonist/ 5-HT1A agonist COMT inhibitor

Phase III

–

Phase I

Neuroprotective

A2A antagonist A2A antagonist A2A antagonist AChE inhibitor

Phase III Preclinical Phase I Launched

Neuroprotective Neuroprotective Neuroprotective Cognitive enhancement

Adapted with permission from The Thomson Corporation and Johnston and Brotchie (2004). # 2004 The Thomson Corporation. MAO-B, monoamine oxidase-B; COMT, catechol-O-methyltransferase; AChE, acetylcholinesterase.

dopamine agonists, fully or partially selective or nonselective (Bezard et al., 2003a). D2-selective agonists such as sumanirole were developed based on the concept that the D3 component action of the previous generation of dopamine agonists, such as pramipexole, may be detrimental to the antiparkinsonian effect (Stephenson et al., 2005). The concept of constant dopaminergic stimulation (Chase, 1998) is now leading to the study of new ways of administering dopaminomimetics, such as the transdermal route, for the possibility of giving particularly stable plasma levels (Parkinson Study Group, 2003). Rotigotine is a non-ergot dopamine agonist, acting selectively on D2-receptors, which has been formulated

in a silicone-based transdermal system. The rationale behind this transdermal delivery system is based on the option of having a non-oral DA agonist which may be useful in terms of compliance in patients already assuming many drugs for the oral route and the capability of stable blood levels of a dopamine agonist. Rotigotine patch reaches the steady state in 24 hours and allows stable drug release in the 24-hour period (Metman et al., 2001). Early PD patients (n ¼ 242) were treated in a phase III double-blind, placebo-controlled study against four different doses of rotigotine (4.5, 9.0, 13.5 or 18 mg). The doses of 13.5 and 18.0 mg were superior to placebo at week 11. Side-effects were also more frequent in the active-treatment groups and were qualitatively similar to

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those reported in other studies of dopamine agonists in early PD patients (nausea, application-site reaction, dizziness, somnolence, insomnia, vomiting and fatigue) (Parkinson Study Group, 2003). Local skin reactions were not uncommon (39%), leading to early withdrawal in a few cases. Preliminary positive data are also available for the transdermal delivery of lisuride (Woitalla et al., 2004). 37.3.3.1. Slv-308 SLV-308 is a partial D2D3 agonist and an agonist of 5HT1A receptors, a profile which suggests a good antiparkinsonian action with reduced capability of inducing dyskinesia. Phase II trials in the treatment of PD are under way (Wolf, 2003). 37.3.3.2. Safinamide This is a novel experimental drug combining several pharmacological properties that are potentially useful in the treatment of PD. This drug has the capability of blocking voltage-dependent sodium and N-type calcium channel, therefore inhibiting glutamate release. Safinamide is also a highly selective and reversible inhibitor of MAO-B, decreasing dopamine breakdown and the production of toxic free radicals (Fariello et al., 1998). The peculiarity of this dual mechanism of action offers the possibility that safinamide might be used in PD, but also in the treatment of epilepsy. A recent double-blind trial has shown that safinamide increased in respect to placebo (37.5 versus 21.4%) the percentage of early PD patients improving their motor score by >30% and also improved the motor scores in a subgroup of patients under stable treatment with dopamine agonists (Stocchi et al., 2004).

37.4. Antidyskinetic drugs The pathophysiology underlying treatment-related dyskinesia is not well known and cannot easily be fitted into current models of basal ganglia dysfunction in PD. It may involve altered activity in the projection pathways from the striatum to the globus pallidus, resulting in reduced activity in the output regions of the basal ganglia, i.e. the internal segment of the globus pallidus and the substantia nigra pars reticulata (Papa et al., 1999). Several experimental and clinical studies in parkinsonism have shown that motor fluctuations and LID can be modulated by drugs acting on neurotransmitters other than dopamine, including glutamate, g-aminobutyric acid, norepinephrine, acetylcholine, serotonin, adenosine and cholecystokinin. In numerous cases, the prospect of using specific drugs

to counteract LID was raised by the previously shown efficacy of such compounds in the treatment of other types of dyskinesia. 37.4.1. Glutamatergic drugs Amantadine is an antiviral compound, which has been widely used as a first-line antiparkinsonian drug since 1969, but has only recently been found to act as a noncompetitive N-methyl-D-aspartate (NMDA) glutamatergic antagonist (Chase et al., 2000). Findings from basic science suggesting that NMDA receptor blockade may improve the dyskinetic complications of LD therapy have thus prompted the use of this compound as a specific antidyskinetic drug (Metman et al., 1998a). Following pilot studies showing that amantadine has a favorable effect on LID in a significant percentage of patients with PD, further work has confirmed the beneficial effects of amantadine on motor response complications (Pourcher et al., 1989; Metman et al., 1999; Luginger et al., 2000; Snow et al., 2000; Del Dotto et al., 2001), although some authors have shown that benefit may be short-lived (Thomas et al., 2004). The hope of better-tolerated glutamate antagonists is driving the development of the non-competitive a-amino-3-hydroxy-5-methylisoazole4-propionate (AMPA) antagonists, for example talampanel. Since AMPA antagonists may also have neuroprotective actions, some of the companies now appear to be developing AMPA antagonists for this use, rather than as antidyskinetic drugs (Johnston and Brotchie, 2004). The results of other trials in which familiar drugs have been used in LID are less convincing. For instance, the efficacy of a combination of LD and anticholinergic drugs in parkinsonian patients to reduce both parkinsonian symptoms and biphasic dyskinesia was only demonstrated in a single trial (Pourcher et al., 1989). The addition of 5-methoxy 5-N, N-dimethyl-tryptamine, a non-selective serotonin agonist, slightly reduced dyskinesia but also reduced the antiparkinsonian benefit of LD (Gomez-Mancilla and Bedard, 1993). More recently, alleviation of parkinsonian symptoms without the development of dyskinesia has been reported in both MPTP-lesioned monkeys and other experimental animals by using adenosine A2A receptor antagonists and NR2B-selective NMDA glutamatergic antagonists (Kanda et al., 1998, 2000; Grondin et al., 1999; Steece-Collier et al., 2000; Bibbiani et al., 2002; Lundblad et al., 2003). The potential symptomatic use in PD of drugs acting on serotonergic and adenosine receptors will be discussed in more detail in the next part of this chapter.

INVESTIGATIONAL DRUGS A summary of the various drugs which have been successfully tested in LID in controlled trials on humans is shown in Table 37.3 (Colosimo and Craus, 2003). Data for this synopsis were identified by means

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of searches, using the search terms ‘Parkinson’s disease’, ‘levodopa’ and ‘dyskinesia’ on Medline and references from relevant articles; numerous articles were also identified through searches in the authors’

Table 37.3 Symptomatic drugs for LID as proven by controlled trials Compound

Mechanism of action

Reference and study design

Dose*

Ritanserin

Selective serotonergic 5-HT2 antagonist

Meco et al. (1988): Single-blind, placebo-controlled, cross-over study

Buspirone

Serotonergic 5-HT1A-agonist

Fluoxetine

Selective serotonin reuptake inhibitor b-Adrenergic blocker

Bonifati et al. (1994): Double-blind, placebo-controlled, cross-over study Durif et al. (1995): Videotape randomized evaluation Carpentier et al. (1996): Videotape randomized evaluation Durif et al. (1997): Videotape randomized evaluation Durif et al. (2004): Double-blind, parallel-group, placebo-controlled, multicenter trial Metman et al. (1998a): Double-blind, placebo-controlled, cross-over study Metman et al. (1999): Double-blind, placebo-controlled, cross-over study Luginger et al. (2000): Double-blind, placebo-controlled, cross-over trial Snow et al. (2000): Double-blind, placebo-controlled, cross-over trial Del Dotto et al. (2001): Acute doubleblind, placebo-controlled study Metman et al. (1998b): Double-blind, placebo-controlled, cross-over study Metman et al. (1998c): Double-blind, placebo-controlled, cross-over study Manson et al. (2000a): Randomized, placebo-controlled, double-blind, cross-over trial Rascol et al. (2001b): Randomized, double-blind, placebo-controlled study Sieradzan et al. (2001): Randomized, double-blind, placebo-controlled, cross-over trial Olanow et al. (2004): Prospective, 6month multicenter open-label doserising study and videotape evaluation Fox et al. (2004): Randomized, doubleblind, placebo-controlled, cross-over, acute-challenge study

Mean dosage of 21.4 mg (range 10–30 mg), 3 a day 10 mg, 2 a day

Propranolol Clozapine

Amantadine

Dextromethorphan

Dopaminergic D4/D1antagonist, serotonergic 5-HT2 antagonist, anticholinergic?

Non-competitive NMDA glutamatergic antagonist

NMDA glutamatergic antagonist

Olanzapine

Dopaminergic D1/D2/D4antagonist

Idazoxan

a2-Adrenergic antagonist

Nabilone

Cannabinoid receptor agonist

Sarizotan

Serotonergic 5-HT1A full agonist, dopaminergic D2/D3/D4 weak antagonist? Opioid antagonist

Naloxone

*Unless indicated, the dose was given orally; when available, the number of doses per day was given. Adapted with permission from Colosimo and Craus (2003). NMDA, N-methyl-d-aspartate.

20 mg, 2 a day Up to 60 mg a day 50 mg/day Up to 50 mg a day

100 mg, 3–4 a day 100 mg, 3–4 a day 100 mg, 3 a day 100 mg, 2 a day 200 mg in a 2-hour intravenous infusion Range, 60–120 mg/day Up to 180 mg a day Up to 7. 5 mg/day

10, 20, 40 mg, in single dose 0.03 mg/kg in two doses Up to 10 mg/day

0.4 mg/kg per min in intravenous infusion

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extensive files. Abstracts and reports from meetings were also included. Several other drugs have been reported to improve LID in case series or uncontrolled trials, e.g. methysergide (Gomez-Mancilla and Bedard, 1993), physostigmine (Tarsy et al., 1974; Gomez-Mancilla and Bedard, 1993), estrogens (Gomez-Mancilla and Bedard, 1992), progesterone (Gomez-Mancilla and Bedard, 1992), riluzole (Merims et al., 1999), mirtazapine (Meco et al., 2003), quetiapine (Oh et al., 2002), magnesium sulfate (Chassain et al., 2002), alpha-amino-3hydroxy-5-methyl-4-isoxazole (a propionic acid receptor antagonist) (Silverdale et al., 2002), 3,4-methylenedioxymethamphetamine (ecstasy) (Iravani et al., 2003) and cannabis (Venderova et al., 2004). These pilot studies should encourage, when appropriate, larger double-blind controlled trials. 37.4.2. Noradrenergic drugs A key abnormality most likely underlying LID is the overactivity of the direct striatal output pathway connecting the striatum with the output regions of the basal ganglia. Adrenergic a2-receptors are present in the basal ganglia and several experimental studies have shown that they occur in high density in the rat and mouse striatum, in a position likely to influence the direct or indirect striatal motor outputs (Scheinin et al., 1994; Holmberg et al., 1999; Papa et al., 1999; Bezard et al., 2001; Zhang and Ordway, 2003). As it has also been suggested that activation of a2adrenergic receptors can facilitate movements produced by activation of the direct pathway, it is possible that enhanced a2-adrenergic receptor stimulation may contribute to the pathophysiology of LID (Hill and Brotchie, 1999). Other studies have indicated that dopaminergic transmission in the striatum can also be influenced by ß-adrenergic activity; the density of ßadrenergic receptors is one of the highest in the striatum and the local release of dopamine is increased by isoproterenol when applied in vivo into the caudate nucleus or in vitro on rat striatal slices, an effect that is prevented by propranolol (Reisine et al., 1982). In addition, motor behavior studies in animals on dopamine–norepinephrine interactions have shown that the noradrenergic systems in PD are impaired and this probably contributes to both motor and affective symptoms observed in this condition (Burn, 2002). These observations have encouraged studies on drugs acting on the noradrenergic system. Ever since the 1980s, the coadministration of yohimbine and LD to MPTP-treated primates has been known to reduce LID without influencing the antiparkinsonian efficacy of this compound (Chopin et al., 1986). Yohimbine

reduces the dyskinetic effect produced by LD, whereas the antiparkinsonian effect is not altered regardless of the dosage. Yohimbine has a variety of pharmacological properties: it is mainly an a-adrenergic receptor antagonist with low selectivity between a1 and a2 subtypes, but also acts as an antagonist at dopamine D2, 5HT1A and peripheral 5-HT2B receptors and as an agonist at 5-HT1D receptors. On the other hand the combination of LD with clonidine, an a2-adrenoreceptor agonist, also reduced LID, whereas at higher doses clonidine blocked both the antiparkinsonian and the dyskinetic effects of LD (Nishikawa et al., 1984; Gomez-Mancilla and Bedard, 1993; Hill and Brotchie, 1999). More recent are the data concerning fipamezole (JP-1730), a 2-indane imidazole a2-adrenergic receptor antagonist which was also able to reduce LID in the MPTP-lesioned marmoset model of PD (Savola et al., 2003): this compound is currently in phase III clinical trials (Peltonen et al., 2002). Besides, in a single clinical trial it has been suggested that administration of low doses of propranolol, a non-selective ßadrenergic blocker, may improve LID in patients with advanced PD (Carpentier et al., 1996). On the basis of these data, idazoxan, a new selective a2-adrenoreceptor antagonist, was developed and tested in animals with experimental parkinsonism and subsequently in patients with LID. Two reports, one experimental and the other clinical, have confirmed that idazoxan has an interesting pharmacological profile, improving LID without a return to parkinsonian symptoms (Fox et al., 2001; Rascol et al., 2001b). Previous experimental data in animals have suggested that, although idazoxan as a monotherapy displays no antiparkinsonian effect, when given in combination with LD it not only reduces the dyskinetic side-effects of LD, but may even extend the antiparkinsonian action of this compound (Henry et al., 1999). The purpose of the experimental study by Fox and coworkers (2001) was to compare the effect of idazoxan on dyskinesia produced by both LD and apomorphine in the MPTP experimental model of PD. The marmosets were treated with MPTP to induce a parkinsonian syndrome. In the first part of the study, only LD (8 mg/kg) or apomorphine (0.075–0.3 mg/kg) was administered in order to establish the severity of the dyskinesia each drug produced. In the second part of the study, doses of apomorphine and LD were individually administered along with either idazoxan (2.5 mg/kg) or vehicle. A neurologist with clinical experience in movement disorders who was blinded to the animals’ treatment then analyzed the videotapes. Part one of the study demonstrated that both apomorphine and LD increased mobility and improved

INVESTIGATIONAL DRUGS bradykinesia and posture scores, when compared with vehicle-treated marmosets. Administration with either apomorphine or LD resulted in a dose-dependent increase in dyskinesia, with dyskinesia present for the entire period of maximal antiparkinsonian action. When idazoxan was coadministered with LD, the median peak-dose dyskinesia score was significantly lower than that observed with LD alone (4 versus 16; P < 0.05), whereas peak posture, bradykinesia or mobility scores were not significantly different. There were no significant differences between LD/idazoxan versus LD alone in the duration of dyskinesia, nor were there any significant differences between the coadministration of idazoxan and apomorphine and apomorphine alone in the median peak-dose dyskinesia score. Idazoxan had no effect on the antiparkinsonian action of apomorphine or in the duration of dyskinesia induced by this compound. By contrast, the action of LD, following the coadministration of idazoxan and LD, lasted longer than when LD was administered alone (250
20 minutes on time versus 130
10 minutes on time; P < 0.05). The authors concluded that the dyskinesia resulting from LD involves adrenoreceptor activation, whereas dyskinesia resulting from apomorphine does not. Indeed, the action of a2-adrenergic antagonists may involve the blockade of the action of norepinephrine synthesized from LD; the hypothesis is that, since dopamine agonists are not metabolized to norepinephrine, idazoxan does not reduce dyskinesia produced by such agents. This should be taken into consideration when trials with new antidyskinetic agents based on acute challenges with apomorphine are planned. In a clinical study, Rascol and coworkers (2001b) assessed the effects of idazoxan on LID in patients with advanced PD. A total of 18 patients were enrolled in this single-oral-dose randomized double-blind placebo-controlled study. The study tested three different idazoxan doses (10, 20 and 40 mg) and placebo. Assessment consisted of a single oral dose of either idazoxan or placebo, followed an hour later by the patient’s usual first morning dose of LD plus an additional 50 mg. A trained physician used the UPDRS to monitor the treatment effect. Patients were videotaped for the assessment of dyskinesia and were identified as either peak-dose or biphasic. Data were analyzed by means of three different measurements: (1) calculation of the area under the curve (AUC) of the changes from baseline in the dyskinesia and UPRDS scores; (2) calculation of the score distribution; and (3) an analysis of the peak-dose and biphasic dyskinesia scores. The AUC analysis revealed a statistically insignificant dose-related reduction for the mean dyskinesia

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AUC in the 10- and 20-mg idazoxan treatment groups (–20 and –40%) as compared to the placebo group. No AUC trend was found in the 40-mg idazoxan treatment group. The severity score distribution indicated a statistically significant treatment effect in favor of idazoxan (20 mg) when compared with placebo (P ¼ 0.01). No significant treatment effects were found in the biphasic and dyskinesia distribution analysis. The antiparkinsonian effects of LD were similar in both the idazoxan and the placebo groups, whereas adverse events were more frequent with idazoxan than with placebo. The results of this study seem to indicate that idazoxan, by blocking a2-receptors, may reduce levels of dyskinesia in PD patients without affecting the antiparkinsonian efficacy of LD treatment. Although the data obtained in these two studies are consistent with each other, they are in contrast with the only other available clinical trial, which recently reported that idazoxan was not beneficial for LID in 8 PD patients (Manson et al., 2000b). Moreover, although not published, a subsequent multi-institutional trial investigating idazoxan as a treatment for LID was negative. The reasons for the negative results were complex and at least partly due to the capacity of trial centers to comply with the protocol and to the safety profile of the drug (early drop-outs), maybe due to inadequate titration (O. Rascol, personal communication). These studies with idazoxan are of theoretical and clinical interest, but they do have several drawbacks: the results of the clinical trial, in particular, are based on a relatively small number of PD patients and only following an acute oral challenge of LD. Moreover, since idazoxan may induce several adverse events, such as hypertension, tachycardia, flushing and headache, it is difficult to ascertain what are the usefulness and benefit-to-risk ratio of idazoxan in the long-term management of dyskinetic parkinsonian patients. In summary, it seems that, though the mechanisms underlying the manifestations and the priming process for dyskinesia have yet to be fully elucidated, nondopaminergic compounds may provide an effective way of limiting the expression of involuntary movements in PD.

37.5. Symptomatic non-dopaminergic drugs Dopamine replacement therapy effectively treats the early motor symptoms of PD. However, its association with the development of motor complications limits its usefulness in late stages of the disease (Nutt and Holford, 1996; Colosimo and De Michele, 1999) and

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a non-dopaminergic approach to therapy might thus provide an effective way of preventing the development of these complications in PD. 37.5.1. Drugs acting at adenosine receptors Adenosine A2A receptors are localized to the indirect striatal output function and control motor behavior. They are active in predictive experimental models of PD and appear to be promising as the first major non-dopaminergic therapy for PD (Johnston and Brotchie, 2004). The initial results from a controlled clinical trial of an adenosine A2A antagonist, theophylline, conducted on 10 patients with PD, have been contrasting (longer beneficial response on akinesia without significant changes in the other clinical parameters of the disease) (Kulisevsky et al., 2002). Istradefylline (KW-6002) is a novel adenosine A2A receptor antagonist designed to treat patients with motor fluctuations and dyskinesias (Jenner, 2005). Istradefylline is currently in phase III clinical trials for efficacy in patients with PD; results from phase II clinical trials demonstrated that it provides a significant reduction in ‘off’ time and increased ‘on’ time with non-troublesome dyskinesia in LD-treated patients with established motor complications and is safe and well tolerated. In a 12-week, double-blind, randomized, placebo-controlled, exploratory study (Hauser et al., 2003), patients with motor fluctuations and peak-dose dyskinesias were randomly assigned to placebo (n ¼ 29), istradefylline (maximum of 20 mg/ day: n ¼ 26), or istradefylline (maximum 40 mg/day: n ¼ 28). As assessed by patient home diary, off time was reduced and severity of dyskinesia was unchanged, whereas the on time with dyskinesia increased. In addition, there is increasing preclinical evidence that A2A receptor antagonists may also have neuroprotective properties (Johnston and Brotchie, 2004). Thus, their eventual use as symptomatic therapy may lead to the identification of disease-modifying properties. 37.5.2. Serotonergic drugs With progressive degeneration of dopaminergic neurons in PD, dopamine formation from exogenous LD increasingly takes place in striatal serotonergic nerve terminals (Bezard et al., 2003b). It is thus not surprising that pharmacologic agents affecting serotonergic nerve impulse activity, by interacting with 5-HT1A autoreceptors, can regulate serotonin release under normal conditions and dopamine release in LD-treated parkinsonian animals. In the latter circumstances, drugs that stimulate these autoreceptors tend to attenuate peak striatal concentrations of dopamine and

prolong its half-life. If 5-HT1A agonists produce the same pharmacologic effects in PD patients, then a reduction in peak-dose dyskinesias and wearing-off fluctuations might be expected. Recent observations in parkinsonian animals support this possibility (Bibbiani et al., 2001). To evaluate this hypothesis, the effects of a selective 5-HT1A agonist, sarizotan, given orally at 2 and 5 mg twice daily to 18 relatively advanced parkinsonian patients, were recently compared with baseline placebo function during a 3-week, double-blind, placebocontrolled, proof-of-concept study (Bara-Jimenez et al., 2005). Sarizotan alone or with intravenous LD had no effect on parkinsonian severity. But at safe and tolerable doses, sarizotan coadministration reduced LID and prolonged its antiparkinsonian response (P < 0.05). The findings suggest that 5HT1A receptor stimulation in LD-treated parkinsonian patients can modulate striatal dopaminergic function and that 5-HT1A agonists may be useful as LD adjuvants in the treatment of advanced PD. In another open-label trial on 64 patients with advanced PD, sarizotan treatment induced a significant reduction in dyskinesia and particularly in troublesome dyskinesia (Olanow et al., 2004). These benefits were obtained without change in total off time or change in UPDRS or activities of daily living scores. Unfortunately, this compound was recently withdrawn from clinical trials. 37.5.3. Drugs acting at synaptic vesicular proteins Levetiracetam (LEV; (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide) is an antiepileptic drug that is approved as add-on therapy in the treatment of partial-onset seizures (Kumar and Smith, 2004). LEV has been shown to reduce LID in preclinical studies of animal models of PD (Bezard et al., 2003c). Furthermore, a few case reports and small open-label studies indicate that LEV may reduce various abnormal involuntary movements, including myoclonus, paroxysmal kinesiogenic choreoathetosis and Meige’s syndrome. The tolerability and preliminary efficacy of LEV in reducing LID in PD patients were evaluated in a prospective open-label pilot study (Zesiewicz et al., 2005). Nine PD patients who were experiencing peak-dose dyskinesias for at least 25% of the awake day and were at least moderately disabled were treated with LEV in doses up to 3000 mg for up to 60 days. The primary outcome measure was the percentage of the awake day that patients spent on without dyskinesia or with non-troublesome dyskinesia (good on time). The mean dose of LEV at endpoint was 625
277 mg/day. LEV significantly

INVESTIGATIONAL DRUGS improved the percentage of the awake day on without dyskinesia or with non-troublesome dyskinesia at endpoint compared to baseline (43
12% versus 61
17%; P ¼ 0.02). Percentage on time with troublesome dyskinesia decreased from 23
10% at baseline to 11
6% at endpoint, although not significantly. There was no significant increase in off time from baseline to endpoint. There was a 56% drop-out rate, in most of the cases due to somnolence. These preliminary data suggest that LEV is a promising drug in PD patients who experience severe peak-dose dyskinesia; as a result, LEV is currently in phase III clinical trials.

37.6. Conclusions Future developments in drug therapy of PD appear to be exciting and it is likely that PD will remain one of the most active areas of drug development in neurology for many years to come. In the near future it will probably be feasible to demonstrate in vivo if drugs act as neuroprotective or even restorative. It is also very likely that there will be improvements in the way physicians may be able to replace dopaminergic loss and more and more attention is expected on new ways of treating non-dopaminergic symptoms. Efforts are expected too in a better characterization and treatment of cognitive disturbances which frequently accompany PD. This chapter is by definition a section which must be intended in evolution. It is possible that by the time of publication some studies will have appeared showing the efficacy or the failure of a certain treatment. We have tried to give an overview of the closest prospective in the new pharmacological strategies in PD.

Acknowledgments The authors thank W. Poewe and O. Rascol for their data on ongoing trials in Parkinson’s disease. M. Bologna and C. Aurilia helped with the manuscript preparation.

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Further Reading Holloway RG, Shoulson I, Fahn S et al. (2004). Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 61: 1044–1053. Parkes JD, Debono AG, Marsden CD (1976). Bromocriptine in parkinsonism: long-term treatment dose response, and comparison with levodopa. J Neurol Neurosurg Psychiatry 39: 1101–1108.