Intravenous amantadine improves levadopa‐induced dyskinesias: An acute double‐blind placebo‐controlled study

Abstract

Experimental evidence suggests that glutamatergic receptor blockade may improve the motor response complications associated with long-term levodopa treatment in Parkinson's disease (PD) patients. Our objective was to evaluate the acute effect of amantadine, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, on levodopa-induced dyskinesias, and to gain further insights into the antidyskinetic mechanism of this drug. Nine PD patients with motor fluctuations and severely disabling peak of dose dyskinesias received their first morning levodopa dose, followed by a 2-hour intravenous amantadine (200 mg) or placebo infusion, on two different days. Parkinsonian symptoms and dyskinesias were assessed every 15 minutes during the infusion and for 3 hours thereafter, while patients were taking their usual oral antiparkinsonian therapy, by means of Unified Parkinson's Disease Rating Scale (UPDRS, motor examination), tapping test, and a modified Abnormal Involuntary Movement Scale (AIMS). Intravenous amantadine acutely improved levodopa-induced dyskinesias by 50%without any loss of the anti-parkinsonian benefit from levodopa. This study confirms the antidyskinetic effect of amantadine and strengthens the rationale for using antiglutamatergic drugs in the treatment of parkinsonian motor fluctuations.

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…However, it is interesting that currently no agent, including amantadine, has been given an indication for treatment of LID, or dyskinesia generally, by either the United States Food and Drug Administration (FDA) or the European Medicines Agency (EMA). The action of amantadine is to reduce peak dose, established LID without compromising antiparkinsonian benefits in the mouse (Lundblad et al, 2005), rat NHP , and human (Verhagen Metman et al, 1998dDel Dotto et al, 2001), and nonselective antagonism of NMDA receptors is regarded as the mechanism whereby amantadine, dextrorphan, and dextromethorphan exert their antidyskinetic effects (Blanchet et al, 1996c;Verhagen Metman et al, 1998a,b,c,d;Luginger et al, 2000). However, amantadine is not universally effective (Callagham et al, 1974;Sawada et al, 2010), can be poorly tolerated by some patients, and may elicit psychiatric complications (Postma and Van Tilburg, 1975;Verhagen Metman et al, 1998d).…”

Levetiracetam Potentiates the Antidyskinetic Action of Amantadine in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-Lesioned Primate Model of Parkinson's Disease

“…The noncompetitive NMDA receptor antagonist amantadine exerts a mild antiparkinso-nian action in patients (Butzer et al, 1975) and significantly reduces LID in MPTP-lesioned nonhuman primates (Blanchet et al, 1998). Such an antidyskinetic effect has been confirmed in Parkinson's disease patients with LID (Verhagen Metman et al, 1998a;Verhagen Metman et al, 1998b;Snow et al, 2000;Del Dotto et al, 2001). Unfortunately, the induction of unwanted adverse effects detract markedly from the clinical utility of amantadine (Hayden et al, 1981;Macchio et al, 1993).…”

Amantadines: Experience of Application for Parkinson Disease

“…С одной стороны, его эффективность была продемонстрирована в ряде доклинических исследовани-ях на животных моделях [22,23], затем в открытых [24] и двойных слепых клинических исследованиях развернутых стадий БП [25]. Были получены следующие результаты: ■ Прием амантадина (300 мг/д) уменьшал выраженность дискинезий у 60-70% пациентов [26].…”

“…1). Cерьезные побочные эффекты при применении аманта-дина возникают очень редко и в большинстве случаев не требуют отмены препарата [25,40,41].…”