Recent developments in the pharmacological treatment of Parkinson’s disease

Review

Ashley Publicationswww.ashley-pub.com

1. Introduction

2. Levodopa analogues

3. Dopamine agonists

4. α2-Adrenoreceptor antagonist

5. Adenosine A2A antagonist

6. Agents acting at multiple

receptor types

7. Neuroprotective agents:

CEP-1347, rasagiline and

antioxidants

8. Monoamine oxidase type B

inhibitors

9. Neurorestorative: glial cell line-

derived neurotrophic factor,

leteprinim

10. Expert opinion

For reprint orders, please contact:[email protected]

Recent developments in the pharmacological treatment of Parkinson’s diseasePaul Tuite† & Jennifer Riss†University of Minnesota, Department of Neurology, Minneapolis, MN 55455, USA

Parkinson's disease (PD) is a neurodegenerative disorder associated with theloss of dopaminergic neurons in the substantia nigra. The decline ofdopamine leads to motor dysfunctions manifested as tremor, rigidity andbradykinesia. The pharmacological treatment of choice for the past 30 yearshas primarily been the dopamine precursor levodopa. Although it is the mosteffective treatment available, it is clear that other drugs are needed in orderto sustain a therapeutic benefit and to alleviate fluctuations in mobility (i.e.,motor fluctuations). Furthermore, there is some evidence that levodopa mayhasten the occurrence of motor fluctuations and involuntary movementscalled dyskinesias. Hence, many clinicians delay the use of levodopa andemploy the use of other symptomatic treatments including monoamine oxi-dase type B (MAO-B) inhibitors and dopamine agonists as first-line therapy inde novo patients. Regardless of treatment, the disease continues to progressas there is still no obvious means of altering disease progression (i.e., noneuroprotective therapy), to restore loss of dopamine (i.e., no restorativetherapy) or prevent the disease (i.e. preventative therapy). With disease pro-gression, polypharmacy is common and often employs a combination ofantiparkinsonian agents. There have been some key advances in treatmentwith the advent of MAO-B inhibitors, dopamine agonists and catechol-O-methyltransferase inhibitors; however, the arsenal of drug treatment remainslimited. As the mechanism of PD is further elucidated, novel drug treatmentswill continue to emerge in the areas of preventative, restorative or sympto-matic therapy. Despite the purpose of treatment, the ideal pharmacologicaldrug for PD will include the presence of a safe side-effect profile, a simpledosing schedule, the ability to provide symptomatic relief and the potentialto alter disease progression. The purpose of this article is to examine upcom-ing antiparkinsonian drugs in clinical trials based on their pharmacology,safety and efficacy.

Keywords: adenosine antagonists, dopamine agonists, GDNF, MAO inhibitors, neuroprotective, neurorestorative, Parkinson's disease

Expert Opin. Investig. Drugs (2003) 12(8):1335-1352

1. Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder associated with the loss ofdopaminergic neurons in the substantia nigra. The decline in dopamine neurotrans-mission leads to motor dysfunctions manifested as tremor, rigidity and bradykinesia.There is presently no cure for PD, although several pharmacological agents are rou-tinely used to manage symptoms. For the past 30 years, the dopamine precursorlevodopa (L-DOPA) has been the pharmacotherapy of choice. Although levodopa isthe most effective treatment available for alleviating motor symptoms, use of addi-tional medications is necessary in order to sustain a therapeutic benefit and alleviatefluctuations in mobility (i.e., motor fluctuations). With evolution of the disease,

2003 © Ashley Publications Ltd ISSN 1354-3784 1335

Recent developments in the pharmacological treatment of Parkinson’s disease

polypharmacy is common, which now includes the use ofmedications from different pharmacological classes, includingmonoamine oxidase subtype B (MAO-B) inhibitors, dopamineagonists and catechol-O-methyl transferase (COMT) inhibi-tors. These compounds are also used by some clinicians inde novo patients, based on the evidence, albeit controversial,that levodopa may hasten the occurrence of motor fluctuationsand involuntary movements called dyskinesias [1-5]. Unfortu-nately, these and other questions remain unanswered; however,because of enhanced understanding of the pathophysiologyand pathogenesis of PD, in part with the aid of toxic diseasemodels of PD and advances in the study of dopamine metabo-lism, new treatments are being employed.

Although effective, the overall impact of symptomatic med-ications is limited in the long run, since there is no means toprevent PD (i.e., preventative therapy), alter its progression(i.e., neuroprotective therapy) or restore lost dopamine neu-rons (i.e., restorative therapy).

This article will focus on novel pharmacological therapiesthat are currently in Phase II or III studies. It will not coversurgical treatments or dopaminergic cell lines that may beused in transplantation in PD patients. Both preclinical andclinical data will be described where appropriate.

The first section of this review will focus on levodopa ethyl-ester, an analogue of levodopa. Levodopa ethylester was devel-oped in an attempt to improve upon levodopa; currently thegold standard of treatment. The next section will coverdopaminergic agonists such as sumanirole, piribedil, rotigotineand apomorphine. These agents, which interact in distinct wayswith dopamine receptors, have been developed for the sympto-matic management of PD (Table 1). Although drug develop-ment has traditionally focused on dopamine receptors, theemerging role of other receptor types should not be overlooked.Adenosine A2A receptors (which interact with dopamine type 2[D2] receptors), glutamate subtype α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and α-adrenoceptors may also be important as therapeutic targets inthe alleviation of symptoms and possibly in altering the courseof disease. This area of research has led to the development ofcompounds such as fipamezole, KW-6002 and budipine,which will be discussed in the third section of this review (seeTable 1). In the fourth section, data on potential neuroprotec-tive agents will be discussed. Several compounds have recentlyentered clinical trials as possible neuroprotectants based ontheir effects on presumed pathogenic mechanisms (e.g., oxida-tive stress, free radical injury, excitotoxicity or inflammation).The first such purported neuroprotective treatment was theselective MAO-B inhibitor selegiline, which may block the for-mation of free radicals in PD. A relatively new agent, rasagiline(Table 1), an analogue of selegiline, could have neuroprotectiveabilities that arise from its effect on free radical production andon its ability to affect programmed cell death (apoptosis).Another compound, coenzyme Q10, which will not be dis-cussed in this article, is receiving attention because of its role inelectron transport, which may alleviate mitochondrial

dysfunction and exert protective effects in PD [6]. Other com-pounds, such as CEP-1347, are also under investigation due totheir antiapoptotic effects (Table 1). A final area of discussionrelates to research into the development, maturation and suste-nance of dopamine neurons. This line of research has resultedin the discovery of growth factors such as glial cell line-derivedneurotrophic factor (GDNF) and leteprinim, which are nowunder study in clinical trials (Table 1). The goal of this review isto demonstrate the breadth of developments that are forthcom-ing in the management of PD symptoms and for the possiblerestoration and/or neuroprotection of dopamine neurons. Dis-cussion of surgical approaches and dopaminergic cell-line trans-plantation strategies are beyond the scope of this review andwill not be included.

2. Levodopa analogues

2.1 Levodopa ethylester2.1.1 PharmacologyLevodopa ethylester (LDEE, etilevodopa, TV-1203; Teva andLundbeck) is a prodrug of levodopa. LDEE was developed, inpart, to address the variable absorption of levodopa observedin patients with PD. After oral administration, LDEE is rap-idly hydrolysed to levodopa by esterases in the duodenum,where it is rapidly absorbed as levodopa. As a result, LDEEmay provide a more rapid improvement in motor function bydiminishing delayed ‘ons’ from dosing and by reducing medi-cation dose failures (i.e., no-‘ons’) [7].

2.1.2 PharmacokineticsThe pharmacokinetics (PK) of LDEE have been characterisedin several studies. A Phase II, double-blind, randomised, levo-dopa-controlled study was conducted to determine whetheroral LDEE has a faster onset of clinical effect than levodopa/carbidopa (LD-CD). A total of 62 PD patients with delayed‘ons’ and no-‘ons’ were randomly assigned to one of two treat-ment groups: LDEE-CD (5.7 mg/ml LDEE in water) orLD-CD 250/25 mg for 4 weeks, which was phase A. Subjectsreplaced their morning and post-lunch doses with the studymedications. At the end of phase A, all patients beganphase B, an additional 2-week study period where theyreceived 25 mg CD supplementation to their morning andpost-lunch doses to determine if the PK of levodopa improved(i.e., reduced plasma fluctuations). Of the 62 subjects, bloodsamples were collected from 22 patients at baseline, at 2 weeksof treatment in phase A and at the conclusion of phase B.Specimens were obtained after first morning dose and at 10,20, 30, 45, 60 and 120 min after drug administration. Plasmalevels of LDEE and levodopa were analysed using high-per-formance liquid chromatography (HPLC). LDEE levels werebelow the limit of detection of the assay (25 ng/ml) and wereundetectable in the plasma, which is in keeping with the pre-sumed rapid metabolism of LDEE into levodopa in the gutbefore absorption into the bloodstream. The PK profiles ofLD-CD and LDEE-CD confirm the superior profile of

1336 Expert Opin. Investig. Drugs (2003) 12(8)

Tuite & Riss

LDEE-CD. The maximum concentration (Cmax) forLDEE-CD was 33% greater than levodopa after 4 weeks oftreatment (phase A) and 60% greater after 2 weeks of supple-mentation therapy (phase B). Consistent with those findings,the time to peak plasma concentration (Tmax) was lower by53 and 36%, respectively, during the two phases of the studyand the area under the curve AUC0-2h was higher (18 and44%), respectively. However, none of these group differenceswere statistically significant, most likely because of the smallnumber of blood samples [8]. The shorter Tmax and greaterAUC0-2h support the notion that LDEE has a faster onset ofaction and greater bioavailability.

In another study, 29 patients were evaluated in a ran-domised, multi-centre, crossover trial designed to compare thePK of LDEE given in an oral solution, dissolved tablets or swal-lowed tablets, to levodopa given in tablets. Drugs were adminis-tered once-daily for 4 days on an empty stomach with 100 mlof water. Blood samples were collected predose and at 5, 15, 30,45, 60, 90, 120 and 240 min postdose. The latency of transi-tion from ‘off ’ to ‘on’ was recorded. The mean Tmax values didnot differ as a function of LDEE formulations, but as a groupthe LDEE formulations had significantly lower Tmax values (28,29 and 32 min for oral solution, dissolved tablet and swallowedtablet, respectively) than standard levodopa tablets (54 min).

Table 1. Novel Parkinson's disease pharmacotherapies.

Drug class Compound Manufacturer Indication Mechanism Route of administration

Effective doses

Clinical trial Phase

Levodopaanalogues

Levodopa ethylester (etilevodopa, TV-1203)

Teva Pharmaceuticals and Lundbeck

Advanced PD LD precursor Oral 5.6 mg/ml LDEE in water

III*

Dopamineagonists

Apomorphine Bertek Pharmaceuticals

Advanced PD D1, D2 agonist Subcutaneous‡ 2.1 – 6 mg II/III

Piridebil Servier Advanced PD Non-ergot D2/D3 agonist plus α2A/2C antagonist

Oral 150 mg/day II

Rotigotine (SPM-962; N-0923)

Schwarz Biosciences

Early/advanced PD

Selective D2 agonist

Transdermal 9 – 36 mg/day

II/III

Sumanirole Pharmacia/Pfizer Early/advanced PD

Selective D2 agonist

Oral 32 – 48 mg III

Non-traditional receptor types

Fipamezole (JP-1730)

Juvantia Early PD α2-Antagonist Buccal No data in humans

II

KW-6002 Kyowa Hakko Advanced PD Adenosine A2A antagonist

Oral 20 – 40 mg/day

II

Budipine Byk Gulden Pharmaceuticals

Early/advanced PD

GABA, noradrenaline, serotonin, acetylcholine

Oral 20 mg t.i.d. II/III

MAO-B inhibitors

Rasagiline (TV-10123, TVP-1012)

Teva Pharmaceuticals and Lundbeck

Early/advanced PD

MAO-B inhibitor Oral 1 – 2 mg/day III

Neuroprotective Coenzyme Q10

Various Early PD Oxidative metabolism

Oral 1200 mg II

CEP-1347 Cephalon Early PD Mixed lineage kinase inhibitor

Oral 50 mg b.i.d. II/III

Neurorestorative GDNF AMGEN Advanced PD Nerve growth factor

ICV/intraputamenal

4000 µg I/II

Leteprinim (AIT-082, Neotrofin™)

NeoTherapeutics Advanced PD Nerve growth factor

Oral 250 mg b.i.d. II/III

*Development halted. ‡Various formulations in trials.GDNF: Glial cell line-derived neurotrophic factor; ICV: Intracerebroventricularly; LD: Levodopa; LDEE: Levodopa ethylester; MAO-B: Monoamine oxidase type B; PD: Parkinson’s disease.

Expert Opin. Investig. Drugs (2003) 12(8) 1337


The Cmax and AUC levels were not statistically different acrossconditions. This pilot study further substantiates that absorp-tion with LDEE is greater than with levodopa [9].

2.1.3 EfficacyThe RONDO trial studied 220 PD patients with motor fluc-tuations to evaluate the efficacy, safety and tolerability ofLDEE-CD tablets as compared to standard LD-CD therapy[10]. The Phase III trial was a multi-centre, randomised, dou-ble-blind, double-placebo, levodopa-controlled, comparativeparallel group study. Treatment duration was 18 weeks andthe primary outcome measure was change from baseline inmean total daily ‘time-to-on’ for all treatment visits. An addi-tional analysis was performed to determine the absolutechange from baseline to the termination visit in total daily‘time-to-on’. The percentage of responders was also deter-mined for this measure and was defined as the per cent ofpatients that experienced a decrease of at least 45 min in theirtotal daily ‘time-to-on’. Secondary outcome measuresincluded the change in mean daily time ‘off ’, the mean daily‘time-to-on’ and the per cent of dose failures, defined as thepercentage of patients who failed to reach ‘on’ time in 90 min.

Efficacy was assessed with two types of diaries. In one diary,patients recorded the amount of ‘on’ time without dyskinesias,‘off ’ time and ‘on’ time with severe dyskinesias. In the seconddiary, they reported ‘time-to-on’ by considering the time ofdosing relative to the ‘time-to-on’. The results of theRONDO trial were released by Lundbeck and Teva in Janu-ary of 2003. There was no difference between drug conditionson the primary end point measure, thus failing to support sig-nificant superiority of LDEE over levodopa [10].

2.1.4 OpinionLevodopa is currently the cornerstone in the treatment ofPD, although its usefulness is diminished by fluctuatingblood levels over time. LDEE appeared to have promise inovercoming this barrier by producing faster and more stableblood levels. Nevertheless, the failure of LDEE to providesuperior efficacy over levodopa makes it unlikely that thisagent will be further developed. Teva and Lundbeck, thedevelopers of LDEE, are continuing their partnership in PDresearch with efforts to develop the MAO-B inhibitor rasag-iline, as described in Section 8.1.

3. Dopamine agonists

3.1 Apomorphine, piribedil, rotigotine and sumanirole3.1.1 Pharmacology overviewThese agents simulate the action of dopamine at postsynapticreceptors to produce antiparkinsonian effects. There are fivecloned receptor subtypes: D1 – D5 [11]. Each receptor consistsof a seven transmembrane domain linked to GTP-dependentregulatory proteins that regulate adenyl cyclase activity [12].Receptors D1 and D5 stimulate adenyl cyclase activity

(D1-like receptor family), whereas, D2, D3 and D4 inhibitadenyl cyclase activity (D2-like receptor family) [12] (Table 2).

The D1-like receptor family is further subdivided intoD1A and D1B receptors and the D2-like family consists ofD2S, D2L, D2 shorter and D3 and D4 receptor subtypes[12,13]. The existence of various receptor subtypes and thebehavioural effects that they mediate present a special chal-lenge in the development of dopamine agonists. That is,many of these agonists are not selective for a specific receptortype, making it likely that their therapeutic effects will beaccompanied by some side effects. It is unclear whichdopamine receptor family (D1-like versus D2-like) is prima-rily responsible for mediating antiparkinsonian effects, butmany believe that the D2 receptor is more important [18].Some receptor subtypes, such as D2 and D3, also are beingconsidered as targets for the development of neuroprotectiveagents. Although not discussed in this article, studies involv-ing the dopamine agonists pramipexole and ropinirole havebeen completed to evaluate their possible neuroprotectiveeffects and efficacy in reducing the occurrence of motor com-plications (i.e., motor fluctuations and dyskinesias) [14].

Generally, side effects of dopamine agonists include nausea,vomiting, orthostatic hypotension, sedation and hallucina-tions. The occurrence of somnolence has been reported withagonists as well as with levodopa and in some cases has beenassociated with motor vehicle accidents [15-17]. It is alsounknown whether dopamine or other neurotransmitter recep-tors mediate the side effects of these agents. However, neweragents are currently being developed to enhance receptorselectivity in the hopes of improving the benefit/side-effectratio. Some dopamine agonists may result in subjects develop-ing addiction disorders or recurrence of pre-existing addic-tions. Further work is required to delineate these factors asmost evidence is anecdotal [19].

3.2 Apomorphine3.2.1 PharmacologyAlthough the use of apomorphine (APO; Bertek Pharmaceu-ticals) dates back to the 1880s, it has not yet received FDAapproval. Only recently, a randomised, double-blind, placebo-controlled trial of subcutaneously injected APO was com-pleted in the US, despite its use for many years in Europe.APO is a reduced form of morphine that does not have addic-tive properties. It is a dopamine agonist with selectivity forD1 and D2 receptors. Without premedication with anti-nausea medication or careful dose escalation, it is poorly toler-ated in patients because of its propensity to cause vomiting.APO may have particular utility in the reduction of ‘off ’ epi-sodes, in that it produces improved mobility within minutesafter injection. APO appears to have similar efficacy to levo-dopa but has a faster onset of action [20].

Subcutaneous APO is currently under development byBertek Pharmaceuticals and an intranasal formulation is beingdeveloped by Britannia Pharmaceuticals. Phase II clinical tri-

als of the nasal formulation were completed in 2002. The results of this trial are reviewed in Section 3.3.4.


Tuite & Riss

3.2.2 PharmacokineticsDue to the high first-pass effect of APO when given orally, it isadministered in alternate routes to avoid rapid metabolism.Numerous studies have detailed its clinical effect on PD symp-toms by many routes of administration, including parenteral,rectal, subcutaneous, sublingual, transdermal and intranasal [21].

The pharmacokinetic-pharmacodynamic (PK-PD) char-acteristics of subcutaneously injected APO were evaluated insix idiopathic PD patients with ‘off ’ episodes who had beenreceiving APO for a minimum of 1 month [22]. The studyutilised a single maintenance dose (range of 2.1 – 6 mg)given on separate days or a multiple standardised mainte-nance dose (range of 2.1 – 6 mg) given at 90-min intervalsfor three doses. Blood samples were collected predose,10, 20 and 45 min and 1.5, 2, 3 and 4 h after the singledose. Additional blood samples were taken 20 and 90 minafter each multiple dose. Blood samples were assayed byHPLC with tandem mass spectrometric detection. After asingle dose, the mean Tmax was 13.6 min and the eliminationhalf-life was ∼ 43 min. APO blood levels followed first-orderone compartment kinetics. After the multiple doses, themean Tmax was > 20 min, with a mean Cmax of 16 mg/ml.

3.3.3 SafetyIn the study above, subcutaneous APO caused decreases indiastolic and systolic blood pressure. The measurements weretaken repeatedly during the administration of the doses,whether single or multiple, in the standing and sitting posi-tion. Postural changes in blood pressure indicated a slightorthostatic hypotension effect. In addition, heart rates tendedto decrease [22].

In general, APO is associated with nausea, vomiting, ortho-static hypotension, psychosis and sexual dysfunction (e.g.,hypersexuality, APO-induced erections). Repeated injectionstypically cause subcutaneous nodules, sometimes resulting inabscess formation, ulceration and significant scarring [21].Some have suggested that local irritation is likely to occurregardless of the route of administration (subcutaneous, sub-

lingual and intranasal). In rare cases, intravenous administra-tion of APO has been accompanied by venous thrombosis [23].In addition, Coombs-positive haemolytic anaemia has beenreported but at present there are no specific guidelines formonitoring. Nonetheless, baseline haematological assessmentsseem warranted, as does careful documentation of pre-existingconnective tissue disorders, which might suggest a higher riskfor presumed immune-mediated side effects [24].

3.3.4 EfficacyIn the subcutaneous APO study in six patients, the beneficialeffects on motor behaviour were evaluated 4 h after the singledose and 20 and 90 min after the multiple injections using amodified version of the Webster Step-Seconds (WSS) scaleand the Unified Parkinson’s Disease Rating Scale (UPDRS)motor score [22]. Improvements in both the UPDRS motorscores, WSS and dyskinesia scores reached a plateau above anAPO dose of 16 and 22 ng/ml after a single and multipledose, respectively. On average, mobility improved within10 min following injection.

There have been several small clinical trials evaluating theefficacy of different routes of administration of APO. A fewhave demonstrated that the efficacy of APO in PD treatmentrivals that of levodopa [25,26].

A retrospective study of 64 advanced PD patients was con-ducted to determine the benefit of long-term subcutaneousAPO treatment. Of the 64 subjects whose charts were reviewed,45 had been successfully converted to long-term monotherapyand 19 had been able to continue with polytherapy consisting ofsubcutaneous APO therapy along with other oral medications.Of the 19 polytherapy patients, three had previously failedlong-term monotherapy after 6 months. Patients were followedfor a mean duration of 33.8 months (range of 4 – 108 months).The mean maintenance dose of APO was 98 mg per 24 h (mon-otherapy group: 103 mg/24 h; polytherapy group: 93 mg/24 h).In the monotherapy group, the mean maximal reduction in dys-kinesia was 64%, as compared to 30% in the polytherapy group,a statistically significant difference [27].

Table 2. Characteristics of dopamine receptors.

D1 D2 D3 D4 D5

Adenyl cyclase activity

Stimulate Inhibit Inhibit Inhibit Stimulate

Location Cortex, striatum, GPe, STN, GPi/SNr, SNc, limbic system, cardiovascular

Cortex, indirect pathway striatum, limbic, cardiovascular, pituitary

Cortex, limbic system



Receptor-specific side effects

Nausea, vomiting, hypotension, psychiatric disturbances

Drugs ApomorphinePergolide

Apomorphine, pergolide, pramipexole, ropinirole, cabergoline, talipexole, bromocriptine

Bromocriptine, ropinirole, pramipexole

No selective drugs

No selective drugs

GPe: Globus pallidus external segment; GPi: Globus pallidus internal segment; SNc: Substantia nigra pars compacta; SNr: Substantia nigra pars reticulate; STN: Subthalamic nucleus.



In another study, 19 patients with refractory motor fluctua-tions were subsequently followed for a mean of 1.8 years oncontinuous subcutaneous APO. Motor fluctuations decreasedby an average of 65% and symptoms of dyskinesia resolvedcompletely in 4/19 patients during the study period [28].Other studies indicate that the efficacy of APO in improvingmotor function depends on whether continuous or intermit-tent infusions are administered, with the data favouring con-tinuous infusions. In fact, the results suggest that intermittentinfusions may actually worsen dyskinesias [29].

3.3.5 OpinionDespite its proven efficacy against motor fluctuations in PD,the side-effects profile of APO, coupled with its limited cur-rent role in the PD market, may have been a disincentive fordrug companies to perform Phase III clinical trials in the US.In spite of its side-effects profile, however, APO may have aspecific role in PD pharmacotherapy due to its ability to alle-viate ‘off ’ periods. Because of recent data, APO is shortlyexpected to be approved by the FDA for this indication. Inaddition, research from PD mice models suggest that APOmay have neuroprotective effects both in vitro and in vivo,which may result from iron chelation and radical scavengingproperties [30]. These findings are noteworthy; however, dem-onstrating these effects in human clinical trials is unlikely dueto the difficulty in conducting neuroprotective research.

3.4 Piribedil3.4.1 PharmacologyPiribedil (Servier) is a non-ergot dopamine (D2/D3) agonistand a presynaptic α2A/2C-antagonist that is already on themarket in Europe (Trivastal®) as an antiparkinsonian medi-cation. It is active on all major central dopaminergic path-ways (i.e., nigrostriatal, mesocortical, tubero-infundibularand mesolimbic). In 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)-treated primates, piribedil has been dem-onstrated to reverse diskinesias [31]. Piribedil has shownclinical efficacy in reversing motor dysfunction with animprovement of alertness and posture instability whenadministered oral and intravenously [32].

In a recent study, piribedil, when compared to 14 otherantiparkinsonian agents, was found to have a unique bindingprofile, with affinity for multiple receptor types includingD1 – D5, α1, α2, β and serotonin [33]. Of particular relevanceto PD, its effects as an α-antagonist may contribute to itsreported benefit on cognition as well as motor function. Itremains to be determined whether the profile of piribedil willcontribute in a novel way to the management of cognitive andmotor symptoms in PD [33].

3.4.2 PharmacokineticsPiribedil undergoes significant first-pass metabolism whenorally administered. The drug is converted to severalhydroxylated and N-oxide metabolites in humans [34]. There-fore, bioavailability (F) is low (F ∼ 10%) [35]. The hepatic

metabolism of piribedil is essentially unknown but it isthought that its metabolites are inactive on dopamine recep-tors in rat models [36].

Due to its high first-pass effect, a transdermal formulationof piribedil was developed and studied in a randomised,double-blind, placebo-controlled efficacy study in 27 idio-pathic PD patients [37]. The study population includedpatients who were not sufficiently controlled on levodopa.Subjects were randomised into three parallel treatmentgroups and each participant wore two skin patches: two pir-ibedil patches (50 mg/patch), two placebo patches or onepiribedil (50 mg/patch) plus one placebo patch. The studyduration was 3 weeks. Plasma samples were collected atbaseline (1 week prior to patch adhesion) and 1 and 3 weeksafter participating in the study. Samples were assayed usinggas chromatography mass spectrometry with a 1 ng/ml limitof detection. Interestingly, the plasma concentrations wereconsistent among patients, which does not typically occurafter oral therapy. Plasma drug concentrations increased by68% from week 1 to 3 for the single active patch group andincreased by 19% in the double active patch group, suggest-ing saturation of absorption. However, the mean plasmaconcentrations at week 1 and 3 were < 10 ng/ml in bothactive patch groups. Previous studies have demonstratedconcentration-dependent changes in tremor, correlatingwith plasma concentrations of 10 – 30 ng/ml [38].

3.4.3 SafetyIn general, the side effects of piribedil are similar to those ofother dopamine agonists and include gastrointestinal, cardi-ovascular and neuropsychiatric events. In a recent double-blind, randomised, placebo-controlled parallel group studyof 273 idiopathic PD patients, the safety and efficacy ofpiribedil (150 mg) as an adjunct to levodopa was evaluated[39]. Piribedil, given orally at doses up to 150 mg t.i.d., waswell-tolerated. There were six drop-outs in the placebogroup and nine in the piribedil group. Nausea (8.1%) wasthe most commonly reported side effect. Adverse events(AEs) related to sleep included somnolence (2.2 versus0.7%), insomnia (1.5 versus 3.6%) and unintended sleepepisodes (0 versus 0%) in the piribedil-treated and placebogroups, respectively.

3.4.4 EfficacySeveral studies have demonstrated that piribedil is effective inreducing parkinsonian tremor and dyskinesias when used inconjunction with levodopa. For example, a double-blind, ran-domised, placebo-controlled parallel group study was com-pleted in 273 idiopathic PD patients to determine the safetyand efficacy of piribedil as adjunctive therapy [39]. Patientswere randomised to receive placebo or piribedil, which wastitrated up to 150 mg/day by week 5 of 6 months of treat-ment. The primary end point was a reduction in motor signs(i.e., UPDRS Part III scores). Secondary end points were levo-dopa dose reduction, improvement of UPDRS Part II activity


Tuite & Riss

of daily living (ADL) scores, changes in Hoehn and Yahrstaging and effects on the Hamilton Depression Rating Scale(HDRS) scores. The study determined that there was a signif-icant decrease in UPDRS Part III scores in the piribedil grouprelative to the placebo group at day 42 of the study(p = 0.007). Specifically, there was a significant reduction inbradykinesia, posture and gait and rigidity with piribedil(150 mg t.i.d.). These data suggest that piribedil may be abeneficial adjunct to levodopa therapy [39].

In contrast, a subsequent randomised, 3-week, double-blind study of transdermal piribedil in 27 patients with idio-pathic PD failed to demonstrate clinical benefit [37]. Patientswere randomised into three parallel study groups receivingtwo skin patches, each containing either active drug or pla-cebo (see Section 4.3.2 for description). The primary efficacyend point of the study was a decrease in UPDRS motorscores. The secondary end points were the four motorUPDRS subscores (rigidity, bradykinesia, rest tremor and pos-tural tremor), a dopaminergic score and the Schwab and Eng-land ADL index [37]. There were no statistically significantgroup or dose differences in clinical improvements on eitherprimary or secondary end point measures. The lack of clinicalefficacy may have been due to the short treatment duration(3 weeks) and/or insufficient plasma concentrations as dis-cussed above [37]. The most commonly reported side effectswere nausea (11%), vomiting (7.4%) and malaise (7.4%).There were limited complaints of skin irritation due to thetransdermal patch.

More recently, a 6-month, randomised, double-blind, pla-cebo-controlled trial was completed in 115 non-fluctuatingpatients with idiopathic PD whose symptoms were not ade-quately controlled on a stable levodopa dose [40]. The purposeof the study was to confirm that piribedil at 150 mg/dayimproves motor signs in subjects also taking levodopa. Theefficacy criterion was defined as a 30% reduction inUPDRS Part III scores at 4 months. Change from baseline toend of treatment was compared in patients receiving piribedilto those receiving placebo. Piribedil produced a statisticallysignificant decrease in UPDRS Part III scores (56.4% com-pared to placebo, 37.7%, p = 0.040) at 4 months. At6 months, piribedil had decreased scores by 61.8% as com-pared to a 39.6% decrease for placebo (p = 0.020). Thechange from baseline to 4 months did not statistically differbetween groups; however, there was a statistically significantdifference at 6 months (-10 point reduction in the piribedil-treated group versus -6.7 points in the placebo group;p = 0.037). The most common side effects were gastrointesti-nal symptoms [40].

3.4.5 OpinionPiribedil appears to be well-tolerated and has been shown intwo studies to be efficacious as a symptomatic agent.Although piribedil is already in use clinically in Europe, addi-tional positive randomised, controlled studies may be neededbefore approval in the US.

3.5 Rotigotine3.5.1 PharmacologyRotigotine (SPM-962, N-0923; Schwarz Biosciences) is aselective D2 receptor agonist that is currently in Phase IIand III clinical trials. It is being developed by Schwarz Bio-sciences as a once-daily transdermal patch for PD and restlesslegs syndrome. Currently available dopamine agonists, whichare administered orally, have relatively short half-lifes andrequire slow titration and multiple daily dosing. This dosingstrategy produces fluctuating peak and trough plasma concen-trations that seem to underlie fluctuations in motor functionin moderate to advanced stages of disease. Hence, the devel-opment of a transdermal drug delivery system that providessteady-state levels could be clinically useful. Other benefits oftransdermal delivery are that rotigotine avoids first-passmetabolism of the liver and unlike oral dopamine agonists,absorption is not affected by food intake.

3.5.2 PharmacokineticsRotigotine is extremely lipophilic, suggesting that it shouldreadily penetrate the blood–brain barrier. In rat studies, theelimination half-life of rotigotine is 108 ± 7 min and theplasma clearance is 32 ± 4 ml/min/kg [41]. In primates, rotigo-tine steady-state plasma concentration but not clearance, wasdose-dependent and the drug exhibited linear PK [42]. Themetabolites of rotigotine are excreted solely in the bile exceptfor the despropyl metabolite, which is glucuronidated in theliver [43].

In a study of ten advanced PD patients, blood samples weretaken 23 h after patch application following dose escalation(9 – 36 mg). Once the subjects were at their highest dose, anadditional plasma sample was drawn 4 h after patch applica-tion. The drug has linear kinetics between 4.5 and 18 mg perpatch as demonstrated in two of the patients (not all thepatients had PK analysis completed) [44].

3.5.3 SafetyThe Parkinson's Disease Transdermal Clinical Trial Helpingto Assess SPM-962 TDS in Patients Not Receiving Dopamin-ergic Therapy (PATCH) study demonstrated that rotigotinewas well-tolerated with a low frequency of AEs [45]. Therewere three drug-related serious AEs that occurred during thestudy: sleep attack (n = 1); syncope (n = 1); and generalisedtonic-clonic seizure (n = 1). The local skin reactions to thepatch were generally mild, although eight subjects had to dis-continue the patch due to one or more skin reactions. Themost common side effects included nausea, vomiting, dizzi-ness, fatigue and application site reaction.

In a study of ten patients with advanced PD, resting bloodpressure, pulse rates, electrocardiogram (ECG) and laboratorytest values were assessed regularly after dosing. Rotigotine didnot affect vital signs or ECGs but did increase liver functiontests in three subjects. Side effects were measured by selfreport. Side effects were mild and transient and included nau-sea (n = 4), light-headedness (n = 3), hallucinations (n = 3),



confusion (n = 2) and vivid dreams (n = 1). None were doselimiting. Skin reactions included itching at the applicationsite (n = 6), redness (n = 6) and a rash (n = 1) [44].

In general, the side effects reported with rotigotine weresimilar to those commonly reported with other dopamineagonists. Since rotigotine is administered in a patch, however,additional safety evaluations for possible skin reactions arerequired. However, the disadvantage of skin reaction is offsetby the PK benefit of the patch. In the study evaluating274 patients with early PD, most patients rated the patch asgood or excellent in terms of tolerability.

3.5.4 EfficacyIn the late 1990s, a Phase IIb, randomised, double-blind,placebo-controlled, multi-centre trial in the US and Canadawas conducted in 73 moderate-to-severe PD patients [46].Patients were randomised into five parallel groups to receiveeither placebo or one of four doses of a 5 cm patch: 8.4,16.8, 33.5 and 67 mg. Patients applied the patches eachmorning and wore them during waking hours for 21 days.During this time they stopped taking any ongoingdopamine agonist therapy other than levodopa/carbidopa.Levodopa was gradually added back in to control symptomsbased on the clinical judgement of the investigator.

The primary outcome measures in the study includedreduction in daily levodopa/carbidopa doses and improve-ment in symptom control as measured by the Clinical GlobalImpression scale (CGI). Secondary outcome measuresincluded the UPDRS motor section score, timed tappingtests and patient home diaries, which noted the ‘time-to-on’,time ‘on’ with dyskinesias and time ‘off ’. Two of the fourtreatment groups, the 33.5- and 67-mg patch groups, had astatistically significant decrease of levodopa use from baselineto day 21 by 26 and 28%, respectively, versus 7% for pla-cebo. All of the patients tolerated the patch without any seri-ous AEs [46].

A Phase III double-blind, randomised, placebo-controlled,parallel group clinical trial (PATCH study) was conducted tocompare the efficacy, safety and tolerability of four doses ofrotigotine (4.5, 9, 13.5 and 18 mg) versus placebo in316 patients with early stage PD. All subjects had a 1-week pla-cebo run-in period. They were then randomised to one of fourtreatment groups or to placebo. The study consisted of fourphases: titration, maintenance, dose de-escalation and followup. During titration, doses could be increased by 4.5 mg/week.All doses were delivered using up to four patches (1 patch = 0 or4.5 mg rotigotine) placed on the abdomen in a ‘double-dummyfashion’. The maintenance phase lasted 7 weeks followed by a1-week dose de-escalation phase. The follow-up visit occurred2 weeks after dose de-escalation. The primary end point was achange from baseline in UPDRS Part II (ADL) and III (motor)scores at week 11 of treatment. Secondary end points includedchanges in the UPDRS mental, ADL and motor (Parts I, IIand III, respectively) subscale scores and the Hoehn and Yahrstage from baseline to week 11.

Rotigotine produced linear and dose-related improvementin UPDRS (Parts II and III) scores relative to baseline, up toa dose of 13.5 mg, at which point the dose-effect curvereached an asymptote. The 9, 13.5 and 18 mg doses dis-played highly statistically significant differences from the pla-cebo group in the combined motor and ADL UPDRS scoreswith an average of a -4 change from baseline to week 11. Inaddition, the UPDRS (Parts II and III) scores improved at 2,4, 7 and 11 weeks and then returned to baseline after de-esca-lation. In summary, this rotigotine patch study produced astatistically significant reduction of combined ADL andmotor scores in early PD subjects.

In an open-label study of ten patients with advanced PDwith motor fluctuations and dyskinesias, the rotigotinepatch was applied daily for 4 weeks [44]. The dose was esca-lated over 16 days, followed by a maintenance period fromdays 17 – 29 and then a safety follow-up period on days30 – 57. Doses were escalated every 2 – 3 days by 4.5 mgfrom 9 mg to the subject’s maximum-tolerated dose (maxi-mum of 80 mg/day). Subjects received five patches eachmorning and wore them for 24 h on alternating locations oftheir abdomen. The five patches were a combination ofactive and placebo patches to achieve the current daily studydose (9 – 36 mg). The subjects who were taking levodopa/carbidopa continued on this medication; however, it couldbe decreased during the maintenance phase of the study astolerated by the subjects. During ‘off ’ periods, subjectscould request and be given levodopa/carbidopa at any timeduring the study if needed. Subjects also continued anyother concomitant medications such as amantadine, tolca-pone and pramipexole. Subjects completed diaries to docu-ment their condition and the UPDRS Part III motor sectionwas performed on day 1 and then each morning before adose escalation was scheduled to occur. The primary efficacyend point was the total daily levodopa dose. The secondaryend points were measures of enhanced mobility (e.g.,increasing ‘on’ time/lessening ‘off ’ time, and the presence ofmedication-induced dyskinesias) as assessed with self-reportdiaries and clinical observation. Seven of the ten subjectscompleted the trial and were included in the data analysis.Results indicate a substantial reduction of daily levodopadoses with a median change of -53% (1400 to 400 mg/day).There was also a nonsignificant 45% median reduction of‘on’ with dyskinesias and median 62% increase of ‘on’ with-out dyskinesias. The median ‘off ’ time significantlydecreased by 37%.

Additional studies have provided support for the efficacy ofthe rotigotine patch. A Phase II, multi-dose, double-blind, ran-domised, placebo-controlled, four-arm study in 274 advancedPD patients was completed to determine the safety and efficacyof increasing doses of rotigotine as an adjunct to levodopa. Sub-jects who had been on a stable dose of levodopa for 2 weekswere randomised into the following groups: placebo, 9, 18 and27 mg of rotigotine. Patients all began on 9 mg of rotigotineand were dose escalated by 4.5 mg/week into their respective


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treatment groups. Once at their target dose, patients weremaintained for 7 weeks. Following treatment, subjects were fol-lowed for 2 weeks for safety evaluation.

The primary outcome was the change in ‘off ’ time frombaseline to end of treatment [47]. Assessments of ‘off ’ timewere conducted at baseline during the dose-escalation visits(weeks 1 – 5), during the maintenance period (week 8), week12 and at follow up. Assessments were made by patient diariesnoting the ‘off ’ time, which was defined as the time when thepatient had parkinsonian symptoms such as rest tremor,bradykinesia, rigidity or postural instability. Investigators usedthe UPDRS Part III at baseline and during ‘on’ times duringthe study visit as well.

There was a significant decrease in the number of ‘off ’times from baseline to end of treatment in all of the treatmentgroups. The mean changes were -1.81, -2.12, -1.72 and-2.44 h in the placebo, 9, 18 and 27 mg rotigotine, respec-tively. There was a large placebo effect and therefore, no statis-tically significant differences between groups [47]. In asubgroup analysis of patients with Hoehn and Yahr scores inthe severe range (stages 4 and 5), there was a relevant reduc-tion of ‘off ’ time in the active treatment groups versus placebothat appeared to be dose-related. UPDRS Part III scoresimproved more in the treatment groups than in the placebogroup (mean change from baseline to end of treatment) was-4.23, -7.56, -6.20 and -6.91 for the placebo, 9, 18 and27 mg patch, respectively). Despite improvements in ‘off ’time and UPDRS Part III scores, there was no statistically sig-nificant difference between rotigotine and placebo inadvanced PD patients.

Interestingly, rotigotine does appear to produce clinicallyand statistically significant improvement in UPDRS scores inde novo patients (refer to PATCH study above). The primaryoutcome was change in UPDRS Parts II and III scores frombaseline to week 11 (end of maintenance phase). Secondaryoutcomes included the proportion of patients with either a≥ 20 or 30% decrease in UPDRS Part II plus III scores.Results indicate that a statistically significant decrease frombaseline to week 11 was observed in all treatment groups withan apparent ceiling effect between 13.5 and 18 mg/day doses.In addition, a ≥ 20 and 30% decrease in UPDRS Part II plusIII occurred in the 9, 13.5 and 18 mg treatment groups com-pared to placebo, with statistical significance in the 13.5 and18 mg groups.

3.5.5 OpinionRotigotine, a dopamine agonist delivered transdermally, deliv-ers steady-state plasma concentrations within 24 h of patchapplication and may be beneficial as adjunctive therapy inpatients with motor fluctuations. Although orally adminis-tered dopamine agonists can improve motor function byreducing UPDRS scores, the concern over fluctuating plasmaconcentrations remains. By virtue of its PK profile, rotigotineappears to overcome those concerns. Furthermore, Phase IItrials suggest that rotigotine is safe and well-tolerated. Despite

these advantages, rotigotine use in advanced PD patients alsorequires additional medications to alleviate symptoms, whichmay include concurrent orally administered dopamine ago-nists. Nevertheless, rotigotine appears to be efficacious asmonotherapy in de novo patients. Rotigotine is being devel-oped by Schwarz Pharma under license from Aderis Pharma-ceuticals. Enrolment began in June 2002 for Phase III clinicaltrials with results expected in early 2004.

3.6 Sumanirole3.6.1 PharmacologySumanirole (Pharmacia/Pfizer) is a selective D2 agonist. TheD2 selectivity of sumanirole relative to other dopamine ago-nists may result in a superior tolerability profile and predictefficacy in early and advanced PD. The profile of sumanirolemay also confer neuroprotective effects based on animalmodel work evaluating the role of the D2 receptor [14].

3.6.2 PharmacokineticsThere is little information available about the metabolism ofsumanirole. Ex vivo human liver slice studies have demon-strated 20% liver metabolism [48]. In one Phase II, double-blind, randomised, placebo-controlled study conducted inEurope, population pharmacokinetic (PPK) modelling wasconducted with NONMEM® (version 5.1.1) to describe theprofile of sumanirole after oral dosing in 280 subjects with earlyor advanced PD. One aim of the study was to identify patientfactors affecting the PK of sumanirole and to determine therelationship between administration of sumanirole and thedevelopment of orthostatic hypotension [49]. The PPK modelwas achieved using a one-compartment model with first orderabsorption and elimination. The results indicate that the PKcharacteristics of sumanirole are influenced by renal functionbut not race, age or weight. Unexpectedly, orthostatic hypo-tension was more prevalent in patients receiving levodopamonotherapy than in those taking sumanirole and levodopa;however, there was a correlation between orthostatic hypo-tension and sumanirole as the AUC of sumanirole increased[49]. The other relevant PK parameters of sumanirole include amean oral clearance of 38.9 l/h, a mean apparent volume of dis-tribution of 197 l and a mean elimination half-life of 3.5 h [49].

PPK modelling was used to further investigate the PK char-acteristics of sumanirole and in particular, drug–drug interac-tions. It was determined from NONMEM analysis that nodrugs, including levodopa, had any effect on the dispositionof sumanirole. Additionally, the concentration-time profile ofsumanirole was dose linear for a 2 – 48 mg range [48,50].

3.6.3 SafetyThe safety and tolerability profile of sumanirole were studiedin a Phase II clinical trial involving 280 patients [51]. Theoverall percentage of reported side effects was greater in thesumanirole treatment group (69.8%) than in the placebogroup (47.5%). The AEs most often seen in the sumaniroletreatment group included nausea, somnolence and dizziness.



However, the reported side effects were classified as mild-to-moderate and sumanirole was safe and well-tolerated overall.It should be noted that there were no changes from baseline invital signs, laboratory values, ECGs or ratings of sleepiness asmeasured by the Epworth Sleepiness Scale [51].

3.6.4 EfficacyIn a recent Phase II, randomised, double-blind, placebo-con-trolled study, investigators evaluated changes in combinedscores of the UPDRS Part II (ADL) and III (motor portion)in advanced PD patients receiving sumanirole as an adjunct tolevodopa [52]. The primary outcome variable was the changefrom baseline to the end of treatment (week 11) in thesummed scores of the UPDRS Parts II and III scales. The sec-ondary end point was improvement from baseline to week 11on the following measures: sum of UPDRS Parts II and IIIscale total scores; UPDRS II scale total score; UPDRS IIIscale total score; individual scores of the UDPRS II and IIIscales; the Parkinson Dyskinesia Scale; the reduction in dos-age of concomitant levodopa/carbidopa therapy; and the aver-age percentage and severity of the ‘off ’ period.

Sumanirole produced statistically significant improvementin UPDRS Part II and III total scores relative to placebo(-11.17 versus 7.47, p = 0.026). Tremor, handwriting andturning in bed/adjusting clothes showed the greatest meanreductions from baseline. In UPDRS Part III, the greatestmean reductions were seen in finger tapping, rapid alternatingmovements, upper extremity tremors and upper- and lower-extremity rigidity. Sumanirole was as efficacious as levodopaand, unlike levodopa, did not induce dyskinesias [53].

3.6.5 OpinionSumanirole is a selective D2 receptor agonist with minimalliver metabolism. The D2 effects of sumanirole may make thisdrug a candidate for neuroprotective therapy developmentefforts and may result in enhanced tolerability relative to other,less selective, dopamine agonists. Although studies have estab-lished that sumanirole is promising as an adjunctive therapy inmoderate to advanced PD, additional research is being con-ducted to evaluate its usefulness as monotherapy in early PD.An ongoing study is being conducted to compare sumaniroleto ropinirole and placebo in de novo patients and clinicians areanxiously awaiting the outcome of this work. Because of thelack of comparative studies between sumanirole and other ago-nists, it remains unclear if the side-effect profile will be compa-rable. Sumanirole is currently being developed by Pharmaciaand Pfizer and they are expected to file a new drug application(NDA) to the FDA in early 2003.

4. α2-Adrenoreceptor antagonist

4.1 Fipamezole4.1.1 PharmacologyFipamezole (JP-1730; Juvantia Pharma) is a centrally actingα2-adrenoceptor antagonist. JP-1730 has no effect on sero-

tonergic or dopaminergic neurotransmission but doesincrease noradrenergic transmission. Phase II trials of thisagent for advanced PD are ongoing in the US. There is par-ticular interest in assessing the ability of JP-1730 to suppresslevodopa-induced dyskinesias in advanced PD on levodopatherapy. A recent study in MPTP-induced parkinsonian mar-mosets investigated the effect of JP-1730 on dyskinesias and‘on’ time [54].

4.1.2 PharmacokineticsJP-1730 readily crosses the blood–brain barrier. In a Phase I,placebo-controlled, double-blind clinical study of 33 healthyyoung men, JP-1730 was given in ascending doses via buccalspray. This formulation was of interest because of its hypothe-sised ability to provide quick relief of levodopa-induced dyski-nesias due to its rapid rate of absorption. Volunteers weregiven either single-ascending doses of JP-1730 (0.75, 1.5, 3,7.5, 15, 30, 60 and 90 mg) or placebo. Safety was evaluated byECGs, vital signs and AE reporting. JP-1730 was rapidlyabsorbed and there was little difference in the Tmax as a func-tion of dose. The elimination half-life ranged from 1.47 to3.16 h at 0.75 – 90 mg doses, respectively. The Cmax and AUCare linearly correlated at doses up to 90 mg [55].

4.1.3 SafetyThere was little effect of JP-1730 on blood pressure, heart rateor QTc intervals. There was self-limiting buccal redness andwhitening after administration of this formulation.

4.1.4 EfficacyThe only ‘efficacy’ data currently available for JP-1730 arefrom studies with laboratory animals. In MPTP-inducedparkinsonian marmosets, twice-daily dosing of JP-1730(10 mg/kg) combined with levodopa (12 mg/kg) was com-pared to twice-daily levodopa monotherapy (12 mg/kg). Byday 9 of levodopa treatment, the animals exhibited severedyskinesias. Combined administration of JP-1730/levodopadelayed the development of dyskinesias relative to levodopaalone, which did not reach comparable severity until day 19.In addition, the combination therapy did not result in ‘wear-ing-off ’ phenomena as did levodopa monotherapy [54].

4.1.5 OpinionJP-1730 has not yet been studied in patients with PD. Pre-liminary data from animal models suggest that JP-1730may have a role in delaying the a#ppearance of dyskinesiasand reducing ‘wearing-off ’ effects when used as an adjunctto levodopa therapy. JP-1730, despite its lack of study inclinical trials, has been included here because of its novelmechanism of action and delivery method. The fact thatJP-1730 is able to reduce levodopa-induced dyskinesiasquickly indicates that the buccal spray delivery route pro-duces rapid increases in plasma levels and should be pur-sued further in the context of PD. So far, JP-1730 is theonly putative antiparkinsonian medication to be adminis-


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tered by this route. The National Institutes of Health arecurrently sponsoring a Phase II, randomised, double-blind,placebo-controlled efficacy of buccal JP-1730 study inadvanced PD patients.

5. Adenosine A2A antagonist

5.1 KW-60025.1.1 PharmacologyThere are three main types of adenosine receptors in thebrain: A1, A2 and A3. Receptors in the A2 class are seven-trans-membrane, G-coupled proteins involved in motor controland localised in the caudate-putamen, nucleus accumbens andolfactory tubercle [56]. The A2 receptor subtype A (A2A) recep-tor controls the release of acetylcholine and GABA in thestriatum. Blockade of the A2A receptor produces increasedlocomotor activity that may be beneficial in patients with PD.

Novel adenosine A2A antagonist compounds such asKW-6002 (Kyowa Hakko) have been evaluated in primatemodels for antiparkinsonian activity. As hoped, KW-6002,when given orally for 21 days, reversed motor disabilitieswithout causing dyskinesias [57]. In the MPTP-treated mousemodel, there is evidence that A2A antagonists, includingKW-6002, may have neuroprotective effects mediated by sig-nificant MAO-B inhibitory properties in vitro (dissociationconstant for an inhibitor [Ki] of 21 – 28 µg/ml) [58].

The extent of the neuroprotection engendered byKW-6002 is not yet fully appreciated. Additional studies arein development and should further elucidate this issue.KW-6002 is also in Phase II trials for the treatment of depres-sion in Japan and Europe.

5.1.2 SafetyIn a 12-week, Phase I, parallel-group, single-blind, placebo-controlled trial, Hubble et al. randomly assigned 83 patientswith advanced PD to one of three treatment groups: placebo(n = 29), KW-6002 in escalating doses up to 20 mg/day(n = 26) or KW-6002 in escalating doses up to 40 mg/day(n = 28) [59]. The primary outcome measures were patientself-reported on/off assessments made at home and clini-cian-rated on/off assessments made during a study visit. Sec-ondary end points included the UPDRS Part IV-A(dyskinesia) subscale, the Parkinson Dyskinesia Scale andthe Modified Goetz Dyskinesia Rating Scale. Of the original83 subjects, 65 completed the study. Drop-out rates weresimilar in all treatment arms. Safety events were recorded ona clinician-administered AE questionnaire. KW-6002 andplacebo were similar in their AE profiles with the exceptionof nausea and elevated serum lipid levels in the active drugconditions. Nausea, which rarely led to treatment with-drawal, was two to three times more prevalent in theKW-6002 treatment groups than in the placebo group.Lipid levels were elevated by 7% in all active treatmentgroups but not in the placebo group. Other reported AEswere equally distributed among all treatment groups.

5.1.3 EfficacyIn the same study, subjects’ home diaries revealed ‘off ’ timedecreased more with KW-6002 than with placebo(p = 0.008). Specifically, patients had an average of 1.7 moreawake hours with good mobility (the ‘on’ state; p = 0.004) inthe active drug condition. This effect approached signifi-cance when based on the investigators’ on/off 8-h assessmentratings (p = 0.054). Changes in the secondary end points ofdyskinesia scores were not statistically different among treat-ment and placebo.

5.1.4 OpinionKW-6002 is effective at prolonging ‘on’ time but has notshown any significant reductions in dyskinesias. KW-6002appears to be generally safe and well-tolerated with the excep-tion of nausea. Presently, its focus seems appropriate in reduc-ing ‘off ’ time in patients, which makes it a promising agent inthe treatment of PD. Preliminary data indicate that KW-6002may also have potential effects as a neuroprotective agent; how-ever, further studies need to be conducted in animals andhumans. Perhaps, the usefulness of KW-6002 may be twofold;effective at reducing ‘off ’ time and neuroprotective as well.

6. Agents acting at multiple receptor types

6.1 Budipine6.1.1 PharmacologyAs drug development efforts evolve, drugs with more complexmodes of action are increasingly being studied. Budipine (BykGulden Pharmaceuticals) is an example of such an agent. It hasaffinity for multiple receptor sites, including GABA, noradren-aline, serotonin and acetylcholine receptors [60]. Budipine actsprimarily by indirectly activating striatal dopamine receptors torelease dopamine. Budipine also acts as an MAO-B inhibitorand stimulates dopamine re-uptake receptors to produce aro-matic L-amino acid decarboxylase. In addition, budipine antag-onises the effects of glutamate by inhibiting NMDA receptorsat the phenylcyclidine-binding site. Striatal GABA release isalso inhibited. Although it does not directly act on dopaminereceptors, budipine effectively restores dopamine levels in thestriatum; thus, budipine mimics dopamine activation whilesimultaneously activating or inhibiting other receptor systemsthat are involved in PD [60]. These relatively wide-rangingpharmacological effects may provide enhanced therapeutic ben-efit in patients with moderate-to-advanced PD. With advancesin PD research, it has become apparent that there are a multi-tude of symptoms that are not dopamine responsive and proba-bly require modulation through other neurotransmittersystems. Studies of budipine for other indications have beenreported in the literature for 20 years but its evaluation in thecontext of PD is still developing.

6.1.2 PharmacokineticsIn an open-labelled, randomised, three-way crossover design,18 healthy males were given single oral doses of budipine



(10, 20 or 30 mg) to determine the dose-dependency of itsPK characteristics [61]. Investigators also looked at steady-stateconditions in subjects taking 10 mg t.i.d. to those taking10 mg as a single dose. The results indicated that budipinehas linear kinetics at the doses studied as reflected by linearincreases in AUC and Cmax with increasing doses [61].Budipine is converted to several metabolites and has a longhalf-life of 31 h [62].

6.1.3 SafetyIn general, previous studies have demonstrated thatbudipine is relatively well-tolerated and safe [62-65]. In astudy by Przuntek et al., the most frequently reported AEswere dry mouth, dizziness, loss of appetite, nervousness andvisual dysfunction.

6.1.4 EfficacyA recent double-blind, randomised, placebo-controlled trialexplored the efficacy of budipine as an adjunctive therapy inpatients maintained on other PD medications (levodopa anda dopa decarboxylase inhibitor, bromocriptine and selegiline)[63]. The study included 84 patients with moderate-to-severeidiopathic PD who were randomised into active (budipine,n = 40) or placebo (n = 44) groups for 11 weeks. The currentdopaminergic therapy of the patient was optimised duringthe first 4 weeks of the study and then held stable for 4 addi-tional weeks. At week 9, budipine was initiated and slowlytitrated over 4 weeks in 10 mg/week increments from 20 to60 mg/day. Once the titration was complete, doses of 20 mgwere given three times daily for 11 weeks. If AEs occurred,doses were reduced to 40 mg/day. Budipine significantlyreduced total Columbia University Rating Scale (CURS)scores by a median of 40%. Furthermore, the budipine-treated group had a statistically significant reduction in totalscore and subscores of tremor, rigidity and akinesia as com-pared to placebo (p < 0.001).

6.1.5 OpinionPast studies have statistically shown that budipine is effectivein tremor reduction and levodopa-induced dyskinesias[62,63,65-69]. Budipine may have a future as an adjunctive ther-apy in PD if additional efficacy studies are favourable. Dueto its reduction of tremor, budipine may have a place fortreatment in de novo patients as monotherapy [62,65,66]. Per-haps with this beneficial effect, it may forestall the use oflevodopa and hence delay the appearance of levodopa-induced dyskinesias.

7. Neuroprotective agents

7.1 CEP-13477.1.1 PharmacologyCEP-1347 (Cephalon) is a potent and selective inhibitor ofthe mixed lineage kinase family of enzymes. The inhibitionof these enzymes provides a novel approach for the treatment

of PD by blocking programmed cell death (apoptosis) earlyin the stress-activated kinase cascade. Based on work withanimal models of neurodegeneration, it has been theorisedthat apoptosis may contribute to the dopamine neuronaldegeneration characteristic of PD [65]. For example, inMPTP-treated mice, CEP-1347 at doses of 1 mg/kg/day pro-tected against dopamine neuron loss [70]. Therefore,CEP-1347 is being studied for its potential to delay the pro-gression of neurodegenerative disorders that include PD,Alzheimer’s disease and Huntington’s disease. It is notewor-thy that CEP-1347 does not affect single-photon computedtomography (SPECT)-imaged β-CIT striatal uptake, sug-gesting that administration of CEP-1347 is unlikely to con-found imaging studies of neuroprotection [71].

7.1.2 PharmacokineticsCEP-1347 demonstrated linear PK following either single(ascending from 5 to 125 mg) or multiple doses (i.e., for14 days) in a double-blind, randomised, placebo-controlledstudy in healthy subjects [72]. Studies indicated that there waslittle metabolism of the parent drug, which was 94% recov-ered in the faeces with insignificant recovery in the urine. Themean elimination half-life of CEP-1347 was 24 – 32 h andthe mean Tmax was 1 – 2 h. Food intake did not appear toimpact PK parameters. The PK profile of CEP-1347 was sim-ilar in young and elderly subjects [72].

In a small pilot study of nine patients taking levodopa, itwas determined that CEP-1347 had no effect on the Cmax,Tmax and AUC of levodopa [70].

7.1.3 SafetyThe results of the single-dose study demonstrated no clini-cally significant changes in haematology, ECG recordings orvital signs associated with the use of CEP-1347. AEs weremild-to-moderate, with headache reported most frequently.The multiple dose study also showed no clinically significantchanges in haematology, ECG recordings or vital signs or incognitive function, which was not assessed in the single-dosestudy. The most common AEs reported after repeated dosingwere headache and dizziness [72].

In the first randomised, double-blind, placebo-controlledstudy of CEP-1347 (50 mg b.i.d.), 30 de novo patients, withand without adjunctive levodopa therapy, were studied todetermine safety, tolerability and efficacy, and the effects ofCEP-1347 on the PK-PD of levodopa [70]. Subjects werecomprised of 21 patients who were on stable levodopa ther-apy. Investigators collected UPDRS scores (specific partswere not indicated), vital signs, ECGs, laboratory tests andAEs at baseline and end of treatment (week 4). The mostcommon AEs reported in the CEP-1347 and placebogroups, respectively, included diarrhoea (14 versus 0%),headache (14 versus 11%) and nausea (10 versus 33%).There was no significant change between baseline and end oftreatment for vital signs, laboratory values or UPDRS scoresin either condition.


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7.1.4 EfficacyCephalon and Lundbeck initiated a randomised, double-blind, placebo-controlled, dose-finding Phase II/III study inAugust 2002. Over 800 patients in the US and Canada areprojected to participate for 2 years. The purpose of this studyis to determine whether CEP-1347 delays PD progression.

7.1.5 OpinionCEP-1347 is a novel agent for potential use as a neuroprotec-tive compound in PD. Researchers will have to wait severalyears before efficacy results are released from a large ongoingstudy, although preliminary data with animals are encouraging.

8. Monoamine oxidase type B inhibitors

8.1 Rasagiline8.1.1 PharmacologyNeurons containing MAO-A and MAO-B are located in thestriatum and hypothalamus, respectively. Inhibition of MAOreceptors enhances dopaminergic tone, with MAO-B being moreselective and longer lasting than MAO-A. Rasagiline (N-propar-gyl-1-(R)-aminoindan, TVP-1012, TV-1012; Teva Pharmaceuti-cals and Lundbeck) is a selective, irreversible MAO-B inhibitor.Rasagiline improves upon the initial success of selegiline in termsof its tyramine-potentiating effects. A disadvantage of selegilinewas that it had several amphetamine-like metabolites [73].

Rasagiline produces selective increases in synapticdopamine levels without appreciably affecting serotonergicneurotransmission. This selectivity is probably dose-depend-ent, as selegiline is selective only up to 10 mg. In rodent andnon-human primate models of PD, rasagiline has been shownto protect against MPTP-induced neurotoxicity without alter-ing dopamine concentrations [74,75]. Preclinical studies arebeing conducted to determine whether rasagiline also hasantiapoptotic properties. In vitro it has been shown to preventthe loss of DeltaPsim, a mitochondrial membrane potentialthat is an initial step in apoptosis [76].

8.1.2 PharmacokineticsRasagiline is well absorbed from the gastrointestinal tract andcan readily cross the blood–brain barrier. The therapeuticdose range is 1 – 4 mg administered orally. If the drug is givenchronically for ≥ 3 weeks, rasagiline increases striataldopamine levels. Unlike selegiline, rasagiline is not metabo-lised into amphetamine-like derivatives. It does have an activemetabolite, aminoindan, that has been shown to be effectivein rodent PD models [75].

8.1.3 SafetyRasagiline is generally well-tolerated in healthy volunteers andin patients with early, untreated PD, who have received up to2 mg/day for as long as 10 weeks [77].

In the TVP-1012 in Early Monotherapy for PD Outpa-tients (TEMPO) trial, AEs were similar in the active and pla-cebo groups. The most common side effects were infection

(16%) and headache (12%). There were no significant differ-ences in laboratory values or vital signs between groups, withthe exception of a slight, significant elevation of supine systolicblood pressure (4.04 mmHg, p = 0.02) in the 2 mg treatmentgroup. The 1 mg treatment group did not have a significantdifference versus placebo (2.37 mmHg, p = 0.16) [78].

8.1.4 EfficacyA 6-month, Phase II, randomised, double-blind, placebo-con-trolled clinical trial in 404 early PD patients was performed todetermine the efficacy, safety and tolerability of rasagiline atvarious doses (TEMPO trial) [78]. Patients were randomlyassigned to one of three dose conditions: rasagiline 1 mg/day,rasagiline 2 mg/day or placebo. Study visits were conducted at4, 8, 14, 20 and 26 weeks to evaluate patients using theUPDRS (including mental, ADL and motor subscales),timed-task evaluations, quality-of-life (QOL) assessments andvital signs. In addition, laboratory tests and AEs were evalu-ated at each visit. An ECG was conducted at weeks 14 and 26.Patients were also assessed in terms of the need for clinicallynecessary increases in levodopa. At the 26-week time point,subjects were enrolled in a double-blind active treatmentphase where patients on rasagiline continued their dosing andpatients on placebo switched to rasagiline (1 mg/day) for anadditional 26 weeks.

At 26 weeks, the UPDRS unadjusted mean scores for the1 mg, 2 mg and placebo groups were 24.8 (standard deviation[S.D.] = 12.3), 26.6 (S.D. = 11.8) and 28.4 (S.D. = 14.3),respectively. The unadjusted changes in baseline were 0.1(S.D. = 6.8), 0.7 (S.D. = 5.8) and 3.9 (S.D. = 7.5), respectively.Both active treatments reduced deterioration (i.e., totalUPDRS scores) to a greater extent than placebo (p < 0.001).The adjusted effect size for the total UPDRS was -4.20 for1 mg rasagiline versus placebo (95% confidence interval,-5.66 to -2.73, p < 0.001) and -3.56 for 2 mg rasagiline versusplacebo (95% confidence interval, -5.04 to -2.08, p < 0.001).

8.1.5 OpinionRasagiline appears to have a good safety and tolerability pro-file in patients with early PD and is a useful symptomaticagent. Its neuroprotective properties remain possible butunproven. It also appears to have some efficacy in that itseems to stabilise UPDRS scores when used as an adjunct toantiparkinsonian drugs. Teva is expected to file an NDA forrasagiline in early 2003. A drug approval or launch is esti-mated to occur in 2004/2005.

9. Neurorestorative

There have been some key advances in the understanding ofthe molecular mechanisms of apoptosis and of the repair ofdegenerating neurons. Consequently, a number of potentialneuroprotective and neurorestorative treatments are emergingin preclinical and early clinical studies. In particular, develop-ments in growth factors and the controversial cell replacement



therapy (stem cells) are currently being studied. Discussion ofthe latter approach is beyond the scope of this review.

9.1 Glial cell line-derived neurotrophic factorFor the past 9 years, the development of glial cell line-derivedneurotrophic factor (GDNF) by Amgen has been ongoing inMPTP-induced parkinsonian monkeys in the hopes of devel-oping a restorative treatment for PD. GDNF was given toMPTP-treated rhesus monkeys via intraventricular andintraputamenal minipumps in doses of 5 – 15 µg/day,3 months after lesioning. Pooled results of studies using boththese routes indicate that direct infusion of GDNF into thebrain is effective in restoring dopaminergic function inMPTP-treated rhesus monkeys [79]. Improvement was demon-strated in the reduction of bradykinesia and rigidity. Post-mor-tem brain examination indicated new growth of nigrostriataldopaminergic fibres and cell bodies in the substantia nigra [79].Unfortunately, results in humans with intracerebroventricular(ICV) GDNF administration have not been as successful. Theside effects, as discussed later, were problematic, which wereprobably related to the route of administration [80].

9.1.1 PharmacologyGDNF, a peptide, is known to bind to the α1-subtype of theGDNF family of cell receptors (GNF-α1) and is a growth fac-tor for dopamine neurons [81]. GDNF works through receptortyrosine kinase (RET), which is an abundant enzyme in thebody that exhibits its action by phosphorylating many intra-cellular targets. It is believed that signalling through RET pro-tects against toxin-mediated damage, regenerates axons andrestores injured neurons. In work completed byGrondin et al., dopamine function was restored and MPTP-induced symptoms were reduced at GDNF doses that onlyproduced small increases (3 – 10%) in mean striataldopamine levels [79]. These findings suggest that other mecha-nisms that improve dopamine neuronal signalling may beimportant in symptomatic benefit. Another study demon-strated that the number of neurons expressing tyrosine kinaseincreased by 80% after treatment with GDNF to MPTP-lesioned monkeys. An exciting discussion is ongoing as towhether GDNF may have generated neurons in addition torestoring function [82].

9.1.2 Safety/tolerabilityAn 8-month, multi-centre, randomised, double-blind, pla-cebo-controlled, cohort study compared the effects ofmonthly ICV administration of placebo to GDNF (25, 75,150, 300 and 500 – 4000 µg) in 50 subjects with moderateto advanced PD patients [83]. ICV injections were given viaan implanted port under the scalp. A placebo-controlled,open-label, extension study allowed dosing for up to 20additional months with single doses up to 4000 µg in 16subjects. A total of 92% of patients in the placebo groupreported side effects, as did 100% of the treatment group.Side effects relating to the implantation of the pump

included headache, incisional pain and nausea. There wereserious AEs reported in the treatment groups, includingchest pain (n = 1), abdominal pain (n = 1) and urinaryretention (n = 1) [83]. Other side effects reported were nausea(n = 3), aseptic meningitis (n = 1), hyponatraemia (n = 1)and confusion, delusions and hallucinations (n = 2). A sur-prising side effect included paraesthesias and ‘shock-like’feelings that occurred significantly more often with GDNFand resolved after drug discontinuation. In addition, therewas significant weight loss (p = 0.002) of > 5% of bodyweight associated with GDNF. It is theorised that delivery ofGDNF directly into the spinal fluid was the explanation ofthe untoward number of side effects seen with GDNF [80].

9.1.3 EfficacyICV GDNF did not improve ‘on’ or ‘off ’ total and motorUPDRS scores at any dose in the study. However, in a differ-ent study in the UK, five PD patients were given open-labelcontinuous infusions of GDNF directly into their putamen(as opposed to the ventricular system in the previous study).At 1 year, participants had experienced limited side effects,while they had a significant improvement in medianUPDRS scores from 66 to 30 [84]. Not only does this smallclinical study provide evidence of the efficacy of GDNF butit also suggests that GDNF may be better tolerated whenadministered directly into the putamen than into the ven-tricular system [82].

9.1.4 OpinionIntraputamenal GDNF administration is a novel treatmentstrategy aimed at restoring lost dopamine neurons and byextension, lost function. This is an exciting, albeit invasive,mode of therapy. Side effects from the surgery itself (e.g.,infection and haemorrhage), from the technique (i.e., catheterdislodgement and pump failure) and GDNF itself, maydetract from the utility of this form of therapy. Despite thiscaution, the novelty of neurorestorative therapy has generatedadditional ongoing clinical trials; the results of which areawaited enthusiastically. Considering that this research is in itsinfancy, one must temper the enthusiasm with caution untilmore efficacy and safety data are available.

9.2 Leteprinim9.2.1 PharmacologyLeteprinim (AIT-082, Neotrofin™; NeoTherapeutics), anerve growth factor (NGF), is being evaluated for its utility inthe treatment of neurological disorders. Leteprinim increasesintracellular cAMP, protects against NMDA toxicity in vitroand in vivo (by an NMDA-independent mechanism) andincreases mRNA levels of protective neurotrophic factors.This drug is an analogue of hypoxanthine and is an orally-active NGF agonist. Leteprinim is currently in Phase II trialsas a potential treatment for Alzheimer’s disease, stroke, spinalcord injury, motor neuron disease and PD. An NDA applica-tion is planned for 2003.


Tuite & Riss

9.2.2 PharmacokineticsLeteprinim was well-tolerated in 24 healthy, elderly volunteersat doses of 100 – 2000 mg/day for 7 days. Leteprinim readilycrosses the blood–brain barrier and has an elimination half-life of 38.2 min. The drug leaves the brain via P-glycoproteintransporters. In a Phase II, randomised, double-blind, pla-cebo-controlled trial of leteprinim in patients with mildAlzheimer’s, oral administration of 100 mg resulted in a Tmaxof 2 h, which was linearly and positively correlated with dosesup to 2000 mg [85]. Leteprinim is transported out of the brainby multi-drug transporters and thus, is susceptible to satura-ble mechanism of efflux [86].

A Phase I study, as discussed below, determined the Tmaxand elimination half-life of leteprinim to be 85 min and17.6 h, respectively [87].

9.2.3 SafetyThe Phase I, double-blind, placebo-controlled, single-dose,escalation study was completed in nine healthy elderly vol-unteers [87]. All subjects received single oral doses of eitherleteprinim or placebo weekly for 5 weeks. Six subjects thenreceived escalating doses of leteprinim (0.6, 2, 6 and20 mg/kg) over 4 additional weeks. Two subjects receivedplacebo for the 9-week duration of the trial. There were noreported adverse side effects. One subject withdrew fromthe study due to poor venous access.

9.2.4 EfficacyA Phase II, 12-week, double-blind, randomised, placebo-con-trolled study in PD patients was conducted to determine theefficacy of leteprinim in reducing UPDRS Part III scores.Doses of leteprinim were escalated from 250 to 1000 mg andadministered twice-daily. The company released preliminaryresults from 20 patients in May 2002. The results indicatethat patients experienced statistically significant improvement(values not specified) in motor scores 2 – 3 h after receivingthe first 250 mg dose. Doses of up to 1000 mg b.i.d. werewell-tolerated, although patients experienced worseningsymptoms at the highest doses. Because of this unexpected

pattern of results, NeoTherapeutics has decided to stop thistrial and to initiate a new study where patients are maintainedon lower doses of leteprinim. Aside from its potential effectson UPDRS scores, leteprinim may also have some neuropro-tective qualities and it may also modulate dopaminergic activ-ity. At the 4th Annual Meeting of the American Society ofExperimental NeuroTherapeutics, the company revealedsome data suggesting that leteprinim may have greater neuro-protective effects than riluzole in PD.

9.2.5 OpinionThe novel mechanism of action of leteprinim holds somepromise as a strategy for managing or treating PD, as well asother neurodegenerative disorders. More will be known whenthe full results of the Phase II trial are revealed.

10. Expert opinion

The overall goal of drug development efforts in PD consistsof three strategies: symptomatic, preventative and restorativetreatment. The agents detailed in this article mainly addressthe symptomatic treatment of PD. Although these agents donot necessarily represent ‘significant’ advances (i.e., they maynot be novel strategies) in the treatment of PD, they mayrepresent improvements or alternatives over presently availa-ble medications (i.e., dopamine agonists), by virtue of theirPK or routes of administration. Meanwhile, compoundswith novel mechanisms of action, such as adenosine antago-nists and antiapoptotic agents may find their way to thepharmacopoeia as monotherapy or as adjunctive treatmentsin alleviating symptoms and in slowing disease progression.It is likely that the former will arrive sooner than the latterdue to the challenges of finding a ‘neuroprotective’ agent.However, the development of novel compounds is rapidlyoccurring through the advancement of pharmacogenomicapproaches and with the development of novel PD models(e.g., fruit fly model) [88] that allow for high-throughput,parallel processing of compounds for efficacy in a shorterperiod of time.

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AffiliationPaul Tuite MD1† & Jennifer Riss PharmD2

†Author for correspondence1†University of Minnesota, Department of Neurology, MMC 295, 420 Delaware Street SE; Minneapolis, MN 55455 USA E-mail: [email protected] of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA


Recent developments in the pharmacological treatment of Parkinson’s disease

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