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Pramipexole/Ropinirole Information Summary

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A number of compounds were identified as candidates for further study by the Committee to Identify Neuroprotective Agents in Parkinson's (CINAPS). Of these compounds, Minocycline, Creatine , CoQ10 and GPI 1485 have been selected for testing in the Neuroprotection Clinical Trial.

PRAMIPEXOLE/ROPINIROLE

By binding to dopamine type 2 autoreceptors, pramipexole and ropinirole reduce dopamine release and subsequent dopamine turnover. This is important because dopamine release and subsequent metabolism by MAO generates reactive free radicals which are believed to induce further nigrostriatal damage in Parkinson's patients. There has been some data to suggest that pramipexole induces secretion of a trophic factor that protects dopamine neurons. Important side effects include: orthostatic hypotension, hallucinations, dyskinesias, somnolence, and dry mouth. Both medications manufacturers have also placed a warning pertaining to excessive sleepiness.

Scientific Rationale

Pramipexole (PPX) and ropinirole (RPE) are agonists at dopamine D2 and D3 receptors. PPX has a slightly higher affinity for affinity for D3 receptors as compared to RPE.1 These medications bind post-synaptically to produce their effects on PD-movement related symptoms. By binding to presynaptic D2 autoreceptors, these medications also reduce DA release and subsequent DA turnover.2 This is important because DA release and subsequent metabolism by MAO generates reactive free radicals which are believed to induce further nigrostriatal damage in PD patients.3 This is particularly true in those receiving exogenous levodopa therapy. Although it is hypothesized that PPX and RPE posses neuroprotection properties through an "antioxidant-free radical scavenging " mechanism, there has been some data that suggests that PPX induces secretion of a trophic factor that protects DA neurons.4,5

  1. Pharmacotherapy 2000;20 (1 Pt 2); 17S-25S.
  2. Eur J Pharmacol. 1991;200:65-72.
  3. Brain Res. 1996;742:80-8.
  4. Life Sci. 1999;64 1275-85
  5. J Neural Transm. 1997;20:S8-21.

Animal Model Data

RODENT: PPX was evaluated in 2 rodent models of niagrostriatal (NS) degeneration.1 In gerbils undergoing bilateral carotid artery occlusion, degeneration of NS dopaminergic (DA) neurons occurs over 28-day period in a manner mimicking progressive PD. In this model, PPX-treated gerbils (1 mg/kg by mouth administered for 28 days post-ischemia ) experienced a 36% (p<0.01) less loss of NS DA neurons compared to vehicle treated animals. The effect was specific for NS neurons, in that PPX was not protective of hippocampal regions in this model. Smaller doses of PPX (£ 0.3 mg/kg) given over 28 days were only partially protective. Although the authors suggest that the mechanism by which PPX exerts it effects is by reducing the formation of free radicals by reducing DA turnover however, PPX only marginally decreased DA metabolism (16%), therefore this explanation is unlikely. In this same paper, the investigators evaluated PPX's efficacy in preventing NS loss in mice following methamphetamine exposure (10 mg x 4 given 2 hrs apart). In this model there is gradual loss of NS neurons over a course of 5-days following methamphetamine exposure. After methamphetamine administration, PPX (1 mg/kg x 5 day) or vehicle was given. After the 5-days of treatment, PPX use resulted in a significant reduction in NS cell loss (32%, p < 0.05) when compared to vehicle treated mice. In fact, the mean number of NS cells in the PPX was not statistically different from control animals not exposed to amphetamine.

In mice, PPX's (1 mg/kg x 2, for 12 days) ability to attenuate MPTP-induced (40 mg/kg x 2) midbrain neuronal loss and lipid perioxidation 12 days after injury has been assessed.2 After 12 days, PPX treatment reduced nigral cell loss in the SNpc (55%), ventral tegmental area (56%) and retrorubral (69%) regions as compared to vehicle treated mice exposed to MPTP. In all regions, PPX protective effects on cell loss achieved statistical significance (p <0.01-0.05). This corresponded to a 76% reduction (p < 0.05) in lipid perioxidation in the SN and striatum. PPX also prevented lipid perioxidation PPX also prevented the decrease in striatal DA secretion normally found after MPTP (46%, P<0.05).

PPX was able to reduce the formation of brain free and decrease the levels of DA occurring during CNS of 6-OHDA in rats.3 These effects were only observed with PPX (2 and 10 nmol/2 ml/min) pretreatment (40-minutes before 6-OHDA administration) through a microdialysis catheter. Post-lesion administration had no significant effect. Reductions in free radical formation in the pretreatment groups reached approximately 50% (p<0.05), no trend with increasing dose was observed. Likewise, only pretreatment groups showed a significant decease in DA concentrations (2 nmol/2 ml/min= 73%, p<0.05; 10 nmol/2 ml/min=82%, p<0.01). Interestingly, in this model the free radical scavenger, S-PBN had no significant effect.

The neuroprotective effects of PPX were evaluated in young (8-week) and aged (12-month) MPTP-treated mice.4 Mice were given MPTP (40 mg/day x 5 days-young mice, 20 mg/kg/day x 5 days aged mice) and either 1 mg/kg PPX or vehicle administered 30 minutes before each MPTP injection. PPX (1 mg/kg) or vehicle was continued for a total of 5, 7 or 14 days before striatal DA and histological assessment. In young mice PPX treatment prevented MPTP-induced DA depletion (all treatments, p<0.05). Extending PPX treatment period beyond 7 days did not provide any additional benefit in preventing the reduction in DA concentrations (prevented striatal DA decrease vs vehicle; 5 days-63%, 7-days-47%, 14 days-36%). The preservation of DA concentrations also corresponded to decreased DA turnover and not increased synaptic release. Delaying initiation of PPX treatment after completing of MPTP administration was less effective in preventing decreases in DA concentration. Post-MPTP treatment was less effective in preventing changes in decreases in DA concentrations. These findings paralleled the preservation of TH-positive (confirmed by Nissl staining) SNc neurons. In aged animals, PPX's protective effects were less marked. DA concentration being 16% higher in the PPX group than in the vehicle-treated mice (p<0.05). PPX's ability to preserve SNc neurons was also less in the older animals. These findings advocate earlier treatment during the progression of PD.

OTHER: PPX has been shown to prevent levodopa-induced cytotoxicity (10%, p<0.05) in a dopaminergic cell line (Mes23.5) through an antioxidant mechanisms.5 In cultured mesencephalic cells, PPX was able to stimulate DA neuron growth. This effect was believed to arise from PPX's ability to induce the secretion of a growth factor because heat-inactivation of the culture media prevented the effect in newly added cells.6 In a similar experiment, co-administration of a D3 agonist (7-OH-DPAT) increased PPX's protective effects on mesencephalic neurons, whereas a D3 antagonist (U99194) partially decreased PPX's effect when given alone and totally reverse its effects when given with antioxidants (U101033E or Vit E).7 A selective D2 agonist (U95666) had no protective effects in mesencephalic cells. These findings support the fact that PPX-neuroprotective effects are exerted at least in part by an anti-oxidative mechanism, but one cannot rule out additional mechanisms.

In mice lesioned with 6-OHDA, RPE has been shown to reduce the quantity of free radicals present in the striatum and protected dopaminergic neurons in this region.8 These effects were prevented with pretreatment using sulpiride indicating that RPE's neuroprotective effects stem from its ability to act as an antioxidant.

  1. Brain Res.1996;742:80-8.
  2. Neurosci Lett. 2000;281:167-70.
  3. Brain Res. 2000;883:216-23.
  4. Brain Res. 2001;905:44-53.
  5. Life Sci. 1999;64 1275-85.
  6. J Neural Transm. 1997;20:S8-21.
  7. JPET. 1999;289:202-10.
  8. Brain Res. 1999;838:51-9.

Pharmacokinetics (including blood brain barrier (BBB) penetration)

PPX: Bioavailability >90%, Tmax =1-3 hrs, protein binding= <20%, Vd=400L, Clearance= 500 ml/min, T1/2 = 8-12 hrs. Elimination is primarily renally (90%) by tubular secretion. Elderly PD patients have a 30% decrease in PPX clearance compared to elderly patients alone. PPX has linear pharmacokinetics, however it may display some differences in gender clearance (18-30% less in women than in men).1 ,2

RPE: Bioavailability 55%, Tmax= 1-2 hours, protein binding < 40%, Vd= 7.5 L/kg, Clearance 780 ml/min (decreased 30% in the elderly), T1/2= 6 hrs, undergoes extensive hepatic metabolism by CYP1A2 (major), CYP3A4 (minor).1,3 Although no brain penetration studies were identified, clinical studies cited below suggest both medications do sufficiently cross the blood brain barrier.

  1. Pharmacotherapy 2000;20 (1 Pt 2); 17S-25S.
  2. Mirapex (Pramipexole) Package Insert. Pharmacia and UpJohn, Inc., August 1999.
  3. Requip (Ropinirole) Package Insert. GlaxoSmithKline, March 2001.

Safety/Tolerability in Humans

Both medications have been studied in patients with PD. Important side effects include; orthostatic hypotension, hallucinations, dyskinesias, somnolence and dry mouth. Both medications manufacturers have placed a warning pertaining to excessive sleepiness (Falling Asleep during activities of Daily Living), therefore it is warranted that investigators be aware and monitor for this during clinical trials.

  1. Mirapex (Pramipexole) Package Insert. Pharmacia and UpJohn, Inc., August 1999.
  2. Requip (Ropinirole) Package Insert. GlaxoSmithKline, March 2001.

Drug Interaction Potential

Because PPX is not significantly eliminated by the CYP450 system, nor is it highly protein bound, the risk of drug-drug interactions with PPX is insignificant.1 Because RPE is metabolized by CYP1A2 to a significant extent drug interactions are likely. Ciprofloxacin inhibits RPE elimination. In contrast, theophylline does not. Interestingly, both are CYP1A2 substrates.2

  1. Drug Metab Disp. 1997;25:1211-4.
  2. Clin Pharamcokinet. 2000;39:243-54.

Clinical Trial/Epidemiological Evidence in Human PD

PPX efficacy was evaluated in patients (³ 21 yrs of age) with early idiopathic PD as defined as Stages I-III by the Modified Hoehn and Yahr scale.1 Mean duration of PD before study for both groups was similar (2.3 " 2.5 years) and so was patient age (63 " 10.6). In a 9-week randomized, placebo controlled study. Patients were randomized to either PPX (n=28, 4.5 mg/day maximum) or placebo (n=27) with doses titrated over a 6-week period. Both groups were given selegiline (10 mg/day) during the course of the study. The primary outcome variable was the change in Unified Parkinson's Disease Rating Scale (UPDRS) (Part II- Activities of Daily Living (ADL), Part III-Motor Examination (ME)) as compared to baseline. All assessments were made 2 hours after treatment administration (estimated time to peak PPX concentrations). Three patients form the placebo group did not complete the study (1-worsening PD, 2-did not have idiopathic PD). The PPX-treated patients experienced a 140% improvement over placebo (p =0.002) in ADL scores. Although the PPX-treated patients experienced a larger improvement in ME scores, statistical significance over placebo was not reached (improvement over placebo=44%, p=0.10). Twenty (71%) of PPX-randomized patients reached the target dose without significant adverse effects. In the PPX group side effects requiring dose reduction included; visual hallucinations (n=3), violent dreams/drowsiness (n=1). One patient in each group experienced EEG changes (PR-elongation). PPX patients were also more likely to experience orthostatic hypotension (average decrease=7.5 mmHg, p=0.04). Most cases were asymptomatic. Other side effects included; dizziness, headache, nausea, visual changes. This trial is conclusions are limited because of its short-duration.

The ability of PPX to improve motor function during on and off periods in patients with advanced PD in a 32-week randomized, placebo-controlled study.2 Patients ³ 30 years, with advanced PD defined as stage II-IV by the Modified Hoehn and Yahr scale, still experiencing significant "wearing off" effect on their current carbidopa/levodopa regime. Existing concurrent amantadine, deprenyl and anticholinergic agents were permitted. Treatments (PPX 4.5 mg/day, n=181, placebo n=179) were advanced over 7 weeks and maintained for up to 24 weeks, after which treatments were removed over a 1-week period. Mean age for the groups was similar (63.3 years) as was the mean duration of PD (9.2 years). Approximately 17% of PPX treated patient and 22% of placebo-treated patients withdrew from the study. PPX was able to improve UPDRS ADL both during the "on" (17%, p£ 0.0001) and "off" (19%, p=0.004) periods over that observed with placebo. Motor scores were only assessed during the "on" periods. PPX use resulted in a significant increase in UPDRS ME scores 13% (p=0.01) improvement over placebo. Average percentage of "off" time (24% more "on" time vs placebo, p=0.0006) and severity of PD symptoms during "off" times (12% less severe motor symptoms vs placebo, p=0.01) were also improved with PPX use over placebo. Levodopa dose reduction was also greater (in mg) in the PPX group (vs placebo 22%, p£ 0.0001), however interpretation of this data is limited, in that it does not provide information on the percentage of patients in which dose reduction was possible. Examination of each visit's ADL scale for both "on" and "off" periods shows a relatively constant parallel trend in ADL scores after the end of the titration period. This suggests that the effects of PPX are maintained, however the benefits of PPX do not continue to increase, nor is there and difference in progression of PD between the two treatment groups (i.e., PPX does not prevent progression of PD symptoms, at least as measured by UPDRS ADL scores). Similar findings are observed for UPDRS ME scores. The most commonly reported side effects for the PPX group (minus % placebo) were dyskinesias (20.5%), visual hallucinations (19.3%), confusion (11%), symptomatic hypotension (4.8%), dizziness (4.7%), insomnia (7.1%) and nausea (1%).

PPX's efficacy was evaluated in PD during a 8-month, randomized, placebo-controlled study.3 To be enrolled patients had to have idiopathic PD, be >25 years of age, and be classified as Hoehn and Yahr stage I-III. Patients had to be naïve to DA treatment or not recently received DA therapy (>60 days prior to study). Selegiline (<10 mg/day) use was permitted and randomization stratified accordingly. Patients were titrated to a PPX target dose of 4.5 mg/day (n=164) or placebo (n=171) over a 7-week period, which was maintained for 6-months followed by a 1-week taper before withdrawal. Mean age of the group was 62.7 years and mean duration of PD was 1.8 years among the treatment groups. Seventy-four of PPX were maintained on the maximal dose (4.5 mg/day) and the mean maintenance dose was 3.8 mg/day. For both ADL (vs placebo 27%, p£ 0.0001) and ME (vs placebo 31%, p£ 0.0001), PPX treatment resulted in a significant improvement over placebo. This was consistent throughout the maintenance phase of the study, suggesting tolerance to PPX treatment had not developed. Unlike, the previous study during the terminal portion of the maintenance phase the curves comparing ADL and ME scores for both groups appeared to separate indicating that prevention of the progression of PD may be occurring, however longer study would need to be performed to confirm this hypothesis. A comparable number of patients in both groups completed the study, however the proportion of patients exiting the study because of worsening PD was 4.5-times higher in the placebo treatments (9%) than in the PPX group (2%). Nausea (18.5%), insomnia (12.7%), constipation (11.3%), somnolence (9.5%), visual hallucinations (9.2%) occurred at a significantly higher frequency than placebo (differences PPX% pt with side effects verses with placebo).

PPX (£ 4.5 mg/day, n=79) was compared to placebo (n=83) or bromocriptine (£ 30 mg/day, n=84)) treatment in a 9.5-month study in patients with advanced idiopathic PD.4 Advanced PD was defined as symptoms consistent with Hoehn and Yahr stages II-IV during the "on" period. Patients were included if they were still experiencing PD symptoms and had previously optimized their levodopa therapy. Only concurrent use of Deprenyl was permitted during the study. Treatment doses were titrated over a 12- week period which was followed over a 24-week treatment period after which medication or placebo was removed. Mean age was 62.7 " 9.96 years and median duration of PD before randomization was 7 years. Average maintenance doses were PPX 3.36 mg/day and bromocriptine 22.64 mg/day. PPX and bromocriptine significantly improved UPDRS ADL and ME scores when compared to placebo (ADL, ME ; PPX-22%, p=0.0002, 29%, p=0.0006; bromocriptine 9.2%, p=0.02, 23%, p=0.01). Although there was a trend for PPX to improve PD symptoms more than bromocriptine, UPDRS scores failed to reach statistical significance. However, PPX resulted in a significantly less "off" time with relative percentage improvements being 45.6% for PPX, 29.7% for bromocriptine and 5.8% for placebo. Onset of PPX's effect in reducing "off' time was also more rapid (week 4 vs week 8). Tolerability (as measured by % drop out rates due to side effects) was similar between the 2-active treatment groups (PPX-20%, bromocriptine-20%) with the percentage of patients.

PPX was compared to levodopa as initial treatment in early idiopathic PD (onset < 7 years and Hoehn and Yahr stages I-III).5 Patients were excluded if they had received other medications for PD. Patients were randomized to either PPX (£ 4.5 mg/day, n=151) or levodopa (£ 600 mg/day, n=150). Doses were titrated to effect during a 10-week escalation phase followed by a 21-month maintenance period. The primary outcome variable was the difference in the time to the first occurrence of any of 3 symptoms (wearing off symptoms, dyskinesias, or on-off fluctuations). Secondary assessments included the change in UPDS scores from baseline between the group, the PDQUALIF and the need for supplemental levodopa. A subgroup of patients within each treatment (PPX-42, Levodopa-40) were assessed using [123I] b -CIT imaging to evaluate possible neuroprotective effects of the treatments on DA neurons (i.e., detection of dopamine transporter assessed by b -CIT uptake) after 23.5 months. The mean age (61 yrs) and duration of PD (1.6 yrs) were similar among the treatments. A comparable number of patients in each group completed the study, however a higher percentage of PPX patients (39% vs levodopa 13%, p=0.02) required supplemental levodopa for worsening of symptoms. Among those requiring additional levodopa mean doses were similar PPX-264 " 245 mg/day, levodopa-252 " 245 mg/day). Significantly fewer patients treated with PPX (28%) experienced "end point" symptoms as compared to levodopa (51%, HR 0.45, 0.3-0.66, p<0.001). Among the 3 symptoms, wearing off symptoms and dyskinesias were the most common "end point" symptoms. Results were similar when the study was divided into 6-month intervals and time to study "end point" was reassessed. PPX also resulted in significantly better UPDRS scores when compared to levodopa (vs levodopa HR95%CI; ADL -1.4 (-2.2,-0.5), ME -3.9 (-5.7,-2.1) both p<0.001). Quality of life as assessed by the PDQUALIF was similar for all subscales with the exceptions of sleep (p=0.004) and self-image/sexuality (p=0.02). Levodopa use was associated with a significantly higher score on each of these assessments. Significantly more PPX-treated patients experienced somnolence (vs levodopa; 15.1%, p=0.03), hallucinations (6%, p=0.03) generalized (9.9%, p=0.01) and peripheral edema (10.6%, p=0.002). Thirty-nine patients for each group had the repeat b -CIT SPECT studies done. After 23.5 months, decreases in b -CIT uptake were similar among both treatment groups (PPX: 20 ± 14.2%; Levodopa 24.8 ± 14.4%). These findings fail to support any neuroprotective effect of PPX over traditional levodopa.

PPX's (1.5 mg/day, n=10) ability to spare dopaminergic neurons in early asymmetrical PD was compared to levodopa (300 mg/day, n=10) and placebo (n=10) using [11C] RTI-32 PET (a DAT-specific ligand).6 Binding was assessed at baseline and 6-weeks later after treatment administration. To be eligible for enrollment; patients had to be naïve to levodopa or DA agonist therapy. Doses were titrated over a period of up to 4-weeks. Mean age of patients ranged from 56-61 yrs with mean duration of PD (23-31 months). Mean DAT binding decreased (16-22%) in the various striatal regions in patients treated with levodopa. Although decreases tended to be smaller on the side contralateral to the asymmetry, decreases were bilateral in nature. PPX -treated patients experienced a more variable loss of DAT labeling (3-20%) and as with levodopa treated patients loss was less marked on the contralateral side. Interestingly, placebo-treated patients also experience highly variable change in DAT labeling with no particular side showing a preference for DAT change (loss of 11% to an increase labeling of 1.5%). UPDRS scores significantly improved in both active treatment groups (PPX 28%, Levodopa 33%; both from baseline p<0.05), whereas no improvements were observed in the placebo group (2.2%). These results lead one to question the sensitivity of using RTI-32 PET for research studies. A longer trial with more patients needs to be completed before this can be concluded. The last two studies do not support the fact that PPX is neuroprotective.

A study of the neuroprotective effects of pramipexole, using imaging as the method of detection, was performed in 82 patients. Patients were randomly assigned to receive pramipexole, 0.5 mg 3 times per day with levodopa placebo (n = 42), or carbidopa/levodopa, 25/100 mg 3-times per day with pramipexole placebo (n = 40). Sequential SPECT imaging showed a decline in mean (SD) [123I] -CIT striatal uptake from baseline of 10.3% (9.8%) at 22 months, 15.3% (12.8%) at 34 months, and 20.7% (14.4%) at 46 months approximately 5.2% per year. The mean (SD) percentage loss in striatal [123I]b -CIT uptake from baseline was significantly reduced in the pramipexole group compared with the levodopa group: 7.1% (9.0%) vs 13.5% (9.6%) at 22 months (P = .004); 10.9% (11.8%) vs 19.6% (12.4%) at 34 months (P = .009); and 16.0% (13.3%) vs 25.5% (14.1%) at 46 months (P = .01).9

In a recent Cochran Review including 3 randomized, controlled trials (n=263 patients, RPE, n=164), RPE (8-24 mg/day) therapy permitted a decrease in levodopa dose (180 mg/day over placebo).7 However, this resulted in a 2.9-fold increase in dyskinesias. Comparison with placebo showed no differences in time spent in the "off" state among the RPE or placebo-treated patients. No differences were observed with treatment withdrawals or in the presence of adverse effects. The conclusions of this review are limited, because only 3-trials were evaluated and 2 of the 3 were only 12-weeks in duration and had small sample sizes. In addition, the doses used in 2 of the 3 studies were lower than used in the third study (8-10 mg/day vs 24 mg/day). In a second Cochran review, RPE was compared to bromocriptine for levodopa-induced complications from PD.8 An additional 3 randomized placebo-controlled trials (n=482 patients, RPE, n=257) were evaluated. Duration of the trials ranged from 8-25 weeks. RPE doses varied between 9-24 mg/day and bromocriptine doses ranged form 17.5 to 39.9 mg/day. Improvements in UPDRS ME scales improved comparable for both agents. Although there was a trend for decreased time "off" in RPE group (vs bromocriptine group) the duration did not reach statistical significance. For 2 of the 3 studies, levodopa dose reduction data was available. Overall, RPE use resulted in a 49.5 mg/day decrease in the dose of levodopa. However, the 2 trials were conflicting, one showing greater reduction in levodopa (as compared to bromocriptine) and one showed no difference. With the exception of nausea which was less in the RPE patients, side effects were of a similar frequency in both treatment groups. Both reviews did not support any advantages of RPE use in patients with PD.

  1. Clin Neuropharmacol. 1995;18:338-47.
  2. Neurology. 1997;49:162-8.
  3. Neurology. 1997;49:724-8.
  4. Neurology. 1997 49:1060-5.
  5. JAMA. 2000;284:1931-8.
  6. Neurology. 2001;56:1559-64.
  7. Cochran Database Syst Rev. 2002;Issue 1. Last update: 11/30/00
  8. Cochran Database Syst Rev. 2002; Issue 1. Last update: 7/12/01
  9. JAMA. 2002;287:1653-1661

Last updated July 16, 2008