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Remacemide 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.

REMACEMIDE

Remacemide is a glutamate antagonist, which means it interferes with the function of brain receptors for that chemical. Glutamate, like dopamine, is an important naturally-occurring brain chemical which helps to regulate and control normal body movement. Nigral dopamine depletion in Parkinson's disease results in over-activation of other brain pathways containing glutamate. Thus, reduction or blockade of glutamatergic activity may reduce PD symptoms or alleviate medication side effects. The most common side effects in clinical trials have been mild and include dizziness, somnolence, nausea and vomiting.

Scientific Rationale

Striatal glutamate-dopamine imbalance is important in the pathogenesis of PD. Glutamate corticostriate pathways provide a major source of excitatory neurotransmission from the cerebral cortex. These converge with acetylcholine and dopamine endings on striatal spiny neurons.1 Therefore, NMDA antagonists may modulate this pathway and restore the balance of acetylcholine and dopamine transmission.

Glutaminergic subthalamopallidal pathway in hyperactive after dopamine depletion.2 Excessive transmission from the subthalamic nucleus and subthalamopallidal glutaminergic pathways results in akinesia and ridgidity.3,4 Inhibition of these pathways by glutamate receptor antagonists reverses these motor symptoms.5

Neurotoxic actions of MPTP can be prevented by NMDA antagonist MK-801.6

Glutamate receptor antagonists have been shown to reduce PD symptoms and dopaminergic side effects in rodents and primates, especially when given with levadopa.7-10

It is hypothesized that the pathogenesis of PD may be mediated by glutamate-induced neuronal injury. Therefore glutamate antagonists may be neuroprotective in PD.11, 12

  1. Adv Neurol 1993;60:102-6.
  2. Neuroscience 1987;21:1-40
  3. Science 1990;249:1436-8
  4. Mov Disorders1993;8:421-9
  5. Arch Neurol 1991;48:977-81
  6. Nature 1991; 348:414-8
  7. Ann Neurol 1990;28: 539-46
  8. Ann Neurol 1991;30:717-23
  9. Ann Neurol 1996; 39:574-78
  10. Molec Neurobiol 1996;12:73-94
  11. Ann Neurol 1998; 44:S175-88.

Animal Model Data

RODENT: In reserpine-treated Sprague Dawley rats, low doses of remacemide (RCM) (5 mg/kg) administered with the lowest effective dose of levadopa (75 mg/kg) were able to increase horizontal motor activity significantly (9-fold) over that found with levadopa given alone (p<0.05).1 RCM's additive effect increased with increasing doses with doses of 40 mg/kg increasing motor activity 26-fold (p<0.0025). Adverse effects were not additive. In contrast, RCM (0-40 mg/kg) administered alone did not result in any significant improvement in motor activity nor did it induce any hyperactivity that would inhibit interpretation of study results. This suggests that RCM may be levadopa-sparing, but it requires levadopa to exert its effects.

PRIMATE: In MPTP-pretreated rhesus monkeys, RCM (5 mg/kg) given with the lowest effective dose of Sinemet (25/250) was able to improve clinical symptoms (Modified Monkey Parkinsonism Rating Scale) by 53% over vehicle- treated animals(p<0.0001) and 42% over that found with combination therapy (p<0.0001).1

  1. Ann Neurol 1994;35:655-61.

Pharmacokinetics (including blood brain barrier (BBB) penetration)

In healthy volunteers, the clearance and half-life of RCM is 1.25 ±0.32 L/kg/hr and 3.29 ± 0.68 hrs, respectively.1 RCM has an active desglycyl- metabolite, FPL12925, with a significantly longer half-life 14.72 ± 2.82 hrs. In rodent models, it is hypothesized that RCM enters by passive diffusion with approximately 51% of plasma concentrations reaching the brain.2 However, a larger portion (130%) of RCM is converted to FPL12925 within the brain or at the blood-brain barrier.

  1. Br J Clin Pharmacol 2001;249:249-55
  2. Drug Metab Dispos 1994;22:443-6.

Safety/Tolerability in Humans

No idiosyncratic reactions have been found with RCM for PD or in epilepsy. Likewise, there has been no evidence that RCM exacerbates PD symptoms. Because no patients with psychiatric or dementia have been included in clinical trials, no conclusions can be made regarding RCM worsening these conditions. The most common side effects in clinical trials (see references below) have been mild and CNS (dizziness, somnolence) and GI-related (nausea and vomiting).

See references under trial data.

Drug Interaction Potential

RCM's metabolism is increased by hepatic enzyme inducing medications.1 It also inhibits the metabolism of medications metabolized through CYP3A4.2 RCM does not interact with the highly protein bound drug, valproate.3 This suggests that interactions with other highly protein bound medications is unlikely. One study in PD patients showed that RCM delayed the absorption and decreased the maximal plasma concentration of levadopa, however total exposure (AUC) and elimination of levadopa remained unchanged.4 In this study UPDRS scores were not affected, therefore no significant interaction is likely.

  1. Br J Clin Pharmacol 2001;249:249-55
  2. Expert Opinion Invest Drugs 2000;9:871-83
  3. Seizure 1997;6:179-84
  4. Clinical Neuropharmacology 1999;22:220-25.

Clinical Trial/Epidemiological Evidence in Human PD

STUDY 1:

Design: Randomized, placebo (PLC) controlled trial (N=200, 50-53/treatment) in patients with idiopathic PD within 5 years of onset (Hoehn and Yahr stage 1-3, most 2 or less).1 Patients were not receiving (or requiring) dopamine agonists or other PD medications with the exception of selegiline (if dose stable 2 weeks). Patients with significant dementia, depression or other neurological disorders were not allowed. Efficacy and tolerability of remacemide monotherapy was to be determined in patients with early PD in 6 week study (5-weeks treatment). Target doses (PLC, RCM 150, 300 or 600 mg/day) were titrated over 5 days. All doses were initially administered twice daily (BID), if side effects occurred then doses were given once per day (QID), before withdrawal.

Outcome: No difference among RCM treatment groups and PLC on motor or activities of daily living (UPDRS, Parts II/III) across the study. Slight mental improvement (UPDRS scores) was only observed for the PLC group. No change in mental scores was observed in RCM groups. Patients' and investigators' global impressions did not judge RCM treatment to be beneficial.

Tolerability: No rationale was given for patient withdrawal. Fewer patients receiving RCM 600 mg/day were able to tolerate a BID regime (94% vs 64% PLC, p=0.0002). However, most patients were able to tolerate the QID regime if they failed the BID schedule. Retention rates not significantly different among treatments (PLC 98%, RCM 150 mg-98%, 300 mg-89.1%, 90.6%). Dizziness, nausea, vomiting, somnolence, and insomnia were dose-related side effects observed with RCM. Symptomatic hypotension (per patient report) eosinophilia were observed in the <11% or patients.

Conclusions: No symptomatic benefit was observed with RCM treatment in patients with early PD. However, this was a short-term study with a small number of patients per treatment and with milder PD. Synergy in PD symptoms (? neuroprotective effect) has been noted with RCM and levadopa therapy and was not evaluated. Medication was more tolerated when given QID. Tolerability may improve with slower titration.

STUDY 2:

Design: Randomized, double-blind, placebo-controlled dose-ranging study (32 patients, RCM 22, PLC 10).2 Patients (66 ± 6 years) with moderate to severe PD (Hoehn Yahr stage 2-4) and response fluctuations despite optimal PD treatment. All patients were receiving levadopa therapy and concurrent use of tolcapone and selegiline was allowed. Patients were excluded for any existing GI, hepatic or hematological disease or PD surgery. After randomization (RCM or PLC) patients were followed up to 12-weeks. Doses were started at 150 mg BID with doses increased biweekly by 100 mg/day to a maximum of 400 mg BID or the patient's maximally tolerated dose (MTD). Patients withdrew at the point side effects became problematic.

Outcomes: No statistics were preformed on this study because of the small sample size. There was no change in the percentage "on" time from baseline and the patient's MTD regardless of treatment (RCM 76% to 76%, PLC 76% to 80%). This was also true for the time "on" without dyskinesia. The mean total UPDRS score decreased more in the RCM group (18.6%) as compared with PLC (2%). Scores in the motor and complications of therapy subsets of the UPDRS also decreased in the RCM group (motor 21%, complications 25%), whereas in the PLC there was little change in either score. There was a small improvement in the finger tapping test for the RCM group, and a small worsening in the PLC group. Only, 33% of the RCM treated patients noted improvement on therapy while none did on PLC.

Tolerability: Median MTD for RCM was 450 mg/day and 4 (18%) patients completed the study at the predetermined maximal dose (800 mg/day). The first dose that was less tolerated than PLC was 600 mg/day (50% tolerated 500 mg/day). Approximately 90% of patients reported side effects regardless of treatment. Only 18% of RCM and 40% of PLC treated patients completed the study. Eighteen percent of RCM patients discontinued because of worsening of PD, while 10% of those treated with PLC. The common adverse events with RCM were nausea (39%) and dizziness (37%). The most common symptoms leading to withdrawal with RCM were nausea vomiting, dizziness and hypokinesia. No significant lab findings were observed.

Conclusions: RCM treatment was tolerated in doses < 500 mg/day in the majority of patients. No significant changes were noted in PD symptoms; however 33% of RCM assessed treatment positively. This study is limited because of duration and sample size.

STUDY 3:

Design: Randomized, placebo-controlled trial involving 39 patients (64.3 ± 8.4 years) with idiopathic PD for 13.3 ± 5.8 years.3 Symptoms were classified as severe (> 2 on the UPDRS items for complications of therapy , dyskinesias, and disabling dyskinesias) and a score of >2 on > 2 of the 5 items in the LFADLDS. Subjects were treated with a stable dose of levadopa for 2 to 4 weeks prior to enrollment. Concurrent use of selegiline, dopamine agonists, COMT inhibitors. Patients were excluded if they were taking other medications that could alter PD symptoms or if there was evidence of a psychiatric disorder, dementia or other serious medical condition. After a 2-week baseline phase in which the patient's PD symptoms were assessed, subjects were randomized to receive PLC, RCM 150, 300, or 600 mg/day (9-10/group) and the treatments were continued for 2-weeks. Patients intolerant to BID dose were switched to QID before withdrawal.

Outcomes: There was no difference between the treatment groups in for improvements in the dyskinesia measures, however there was significant improvements observed for the RCM 150 mg/day group for UPDRS "off- time" motor score (treatment effect 6.1, p=0.01) and "off-time" ADL score (TE 4.4, p= 0.004). Trends were observed for improvements in percentage increase in "on-time" (TE 16.2, p=0.04) and "off-time" ADL score (TE 3, p=0.04) for the RCM 300 mg/day group. The RCM 600 mg/day group only experienced improvements in "on-time" ADL (TE 2.5, p=0.04).

Tolerability: All patient's tolerated their treatment assignments for the 2 weeks. The most common side effects were dizziness and GI discomfort and were observed more commonly in the RCM 600 mg/day group. Two patients in the RCM treatment group 1-150 mg, 1-300 mg) developed prolonged QT-intervals, however no mention of concurrent symptoms was given.

Conclusions: Overall RCM was associated with slight improvements in ADL. Little other improvements were observed, particularly with respect to dyskinesias. This may have been due to the short duration of the trial or the fact that the patients self-report diaries were limited in their ability to adequately collect patient information.

STUDY 4:

Design: Randomized, placebo-controlled trial enrolling 279 patients (54-57/group, ages 60.9-64.6 years).4 To be eligible patients had to have idiopathic PD who were Hoehn and Yahr stage 2 to 4 and who experiencing more than 25% of their waking day in the "off-state." Patients must have been receiving a stable dose of levadopa therapy given 4-times daily for = 2 weeks. Concurrent treatment with selegiline, dopamine agonists or COMT inhibitors were allowed, however amantadine and anticholinergic anti-PD or other medications that may interfere with interpretation with the trial were not permitted. Patients with atypical PD, dementia, depression or other medical condition were excluded. Eligible patients were randomized to receive PLC, RCM 75, 150, 300 or 600 mg/day given as two divided doses. Doses were increased over a 5-day period and continuing for a total of 7-weeks with a 1-week follow-up after the dosing period. During the study, patients experiencing intolerable side effects had first had their doses further divided, then the patient's doses were reduced to the next lower dose.

Outcomes: Minimal effects were observed with RCM with respect to increasing "on-time." Effects tended to be better with the smaller doses (150, 300 mg/day). Likewise, improvements were better with the UPDRS motor scale (150 mg/day +1.3, p=0.03; 300 mg/day +1.7, p=0.01 vs PLC -1.7). No other outcome variables (UPDRS mental and ADL scales, Hoehn and Yahr, Schwab and England ADL, CGI, DOT, MMSE, and BDI) showed improvement with RCM. Examination of patient subsets revealed that those with less percentage of daily "on-time," before RCM treatment.

Conclusions: Overall, 88.2% of patients completed the study with or without a dosage reduction. Although, there was no differences were found among treatment groups in the proportion of patients who tolerated their assigned dose, more patients receiving RCM 600 mg/day had to switch to a QID dosing regime than PLC (72% verses 56%). Dizziness, nausea, somnolence, GI intolerance were more likely than PLC. Impaired concentration and hallucinations was reported in < 3% and were distributed equally among the patients. Two PLC (hip displacement, prostrate hyperplasia) and 5 patients had severe adverse events (2-chest pain, 1-pancreatic carcinoma, melena with anemia, and an accidental overdose with mild dizziness, somnolence, dry mouth and sweating.

Overall conclusions suggest that more improvements tended to be observed with RCM in doses of 150, 300 mg/day than lower or higher doses. Doses >300 mg/day were more tolerable administered in four daily doses. When improvements were noted they tended to be minor. Overall, side effects tended to be similar to that observed in other studies.

  1. Neurology 2000;54:1583-88
  2. Clinical Neuropharmacology 2001; 24:133-8
  3. Arch Neurol 2001; 58:1660-68
  4. Neurology 2001;56:455-62.

Last updated July 09, 2008