Famotidine for Levodopa-induced Dyskinesia in PD

Levodopa-induced dyskinesia is a common problem in Parkinson's disease (PD). In particular, targeting non-dopaminergic systems may be an option for reducing dyskinesia without worsening motor symptoms. One such target may be histamine. The central histaminergic system is involved in diverse biological functions including thermoregulation, eating, and sleep; a role in motor activity is suggested by strong histaminergic innervation of the basal ganglia. Histamine H2 receptors are highly expressed in the striatum, particularly on the GABAergic striatal-pallidal and striatal-nigral pathways Histamine H2 stimulation modulates acetylcholine release. Previous studies have demonstrated that blocking acetylcholine with anticholinergic agents can induce chorea. The investigators propose that histamine H2 receptor stimulation decreases acetylcholine in the striatum and increases activity of the direct striatal output pathway, a key component of the neural mechanisms underlying dyskinesia.

The investigators hypothesise that H2 antagonists would reduce activity of the direct striatopallidal pathway and so potentially reduce levodopa-induced chorea

Famotidine has also been assessed in schizophrenia in a small cases series to treat schizophrenia, with tolerability. Clinical experience thus suggests the suitability of using this agent as a histamine H2 antagonist in clinical studies for PD.

The proposed study will be composed of multiple N -of 1 studies performed in a randomized, double-blind, placebo-controlled multiple (4) crossover fashion. Twelve PD patients (thus 12 N-of-1 trials) with levodopa-induced dyskinesia will complete 4 treatment phases; one phase at each of the 3 doses of famotidine and one of placebo. The treatment doses will be: famotidine 40mg/day, 80mg/day, and 120mg/day. The phases will occur in a random order, but each subject will receive each of the treatment doses during the course of the study. After each phase of treatment (14 days), there will be a washout period (7 days, over 10 half-lives of famotidine) followed by a crossover. The primary outcome will be the change in Unified Dyskinesia Rating Scale (UDysRS) between placebo and famotidine at the end of each treatment phase and secondary outcomes will be Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) parts III and IV, Clinical Global Impression (CGI), Lang-Fahn activities of daily living dyskinesia scale (LFADLDS) and assessment of adverse effects.

Eligibility Criteria:
Inclusion Criteria:Eligible patients, male and female, will be less than 80 years of age and be on stable levodopa. Subjects must have stable, bothersome dyskinesia and have an MDS-UPDRS score 2 or greater, on item 4.2. All anti-parkinsonian medications must be unchanged for at least one month prior to study enrollment. Subjects may be taking amantadine at a stable dose for at least one month prior to study onset -

Exclusion Criteria:are prior surgery for PD, Hoehn and Yahr score of 5 when off-medication, history of moderate to severe renal impairment (creatinine clearance \<25 millilitres per minute, dementia (defined by Montreal Cognitive Scale \< 2518 , allergic reaction to lactose, famotidine or other histamine H2 antagonists

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