Rasagiline for the Treatment of Parkinsons Disease I. Etiology1 1. Idiopathic PD 2.

Secondary Parkinsonism: drug induced, environmental toxicities, result of CNS infection, genetic II. Clinical Presentation1 1. Four central motor features: resting tremor, bradykinesia, rigidity, postural instability 2. Non-motor symptoms i. Neuropsychiatric: Depression, anxiety, dementia, psychosis, impulse control disorders (ICDs) ii. Sleep disorders: Insomnia, sleep apnea, daytime somnolence iii. Other: dysphagia, choking, hypersalivation III. Diagnosis2 1. Gold Standard- presence of Lewy bodies at autopsy 2. Criteria- at least 2 of the following: Tremor, bradykinesia, rigidity 3. Diagnosis of exclusion (drug induced, metabolic disorders, trauma, structural abnormalities of the CNS)
IV.

Pathophysiology1, 3 1. Dopamine: inhibitory and excitatory neurotransmitter, depending on the type of dopaminergic receptor it binds to 2. Parkinsons Disease i. loss of dopaminergic neurons leading to depletion of dopamine

. V. Assessment /Monitoring1,3 1. UPDRS i. Allows for an overall measure of disability as well as individual subscores ii. Includes four major parts: mentation, behavior, mood, ADL, motor examination, complications of therapy iii. Allows the assessment of worsening or improvement of PD over time (worsening of symptoms increases score, improvement of symptoms decreases score) 2. Modified Hoehn & Yahr Staging Scale - assesses motor skills 3. Schwab & England Activities of Daily Living - assesses ADL

VI. Treatment Guidelines3 1. Pharmacologic includes: MAO-B inhibitors, Dopamine agonists, Amantadine, Carbidopa/Levodopa, COMT inhibitors 2. Non Pharmacologic: Environmental, diet, exercise, support VII. Pharmacology of Rasagiline3 i. MAO-I Type B inhibitor ii. same class as selegiline BUT does not form amphetamine metabolites VIII. Clinical Trials4 1. The TEMPO Study

i. objective to evaluate the safety and efficacy of the selective monoamine oxidase type B inhibitor rasagiline ii. design - multicenter, randomized, placebo-controlled, double blind, parallel groups iii. methodology: 3 parallel groups: placebo, 1 mg/d rasagaline, and 2 mg/d rasagaline iv. Eligibility: a. Inclusion: Patients over 35 years with at least 2 cardinal signs of
PD and whose disease severity was not greater than Hoehn and Yahr stage III. b. Exclusion: (1) atypical or secondary parkinsonism, (2) unstable medical problems, including CHF of NYHA class II or greater, (3) psychiatric problems that compromised the ability of the subject to give informed consent, (4) a MMSE score of 23 or less, or (5) clinically significant depression. Subjects could be treated with anticholinergic medications, but other antiparkinsonian medications, including levodopa, dopamine agonists, selegiline, or amantadine, were not permitted. Antidepressants (with the exception of amitriptyline, paroxetine, sertraline, fluvoxamine, or trazodone) and sympathomimetics were not permitted.

v. Endpoints: a. Primary: Change in UPDRS score between baseline and week

26.

b. Secondary: changes subscales of the UPDRS, as well as

symptom-based subscores (tremor, rigidity, bradykinesia, and postural instability/gait disorder); changes in the Hoehn and Yahr stage, the Schwab-England ADL scale, Beck Depression Inventory score, timed motor tests, and the Parkinson's Disease Quality of Life (PDQUALIF) scale.

Table 1.

vi. Results of primary and

secondary endpoints: See table 1

vii. Conclusions: a. Rasagiline is an effective therapy for patients with early PD

b. There were no advantages in efficacy for 2 mg/d of rasagiline compared with the 1 mg/d dosage c. Further studies over longer time periods needed to determine long term efficacy

2. The PRESTO Study i. objective to evaluate the safety, tolerability, and effectiveness in patients with PD and motor fluctuations ii. design multicenter, randomized, placebo-controlled, double blind, parallel groups iii. methodology: 3 groups: placebo compared to rasagiline 0.5mg and 1mg iv. Eligibility: a. Inclusion: patients with idiopathic PD with Hoehn and Yahr

stage of less than 5 in the "off" (poor motor function) state, 30 y/o, and experienced at least 21/2 hours in the off state daily. Patients had to receive levodopa at least 3 times daily for at least 2 weeks before screening. Concomitant treatment with stable dosages of dopamine agonists, amantadine hydrochloride, anticholinergics, and entacapone was allowed. b. Exclusion: Patients with atypical or secondary parkinsonism, MMSE score, <24, depressive symptoms (Beck Depression Inventory score, >15), and unstable neurological and medical disorders were excluded.

v. Table two: Results of primary and secondary endpoints

vi. Conclusion: Treatment with rasagaline was well tolerated and was associated with therapeutic benefits. Benefits tended to be greater in patients treated with 1.0 mg versus 0.5 mg, Differences between 0.5 mg and 1.0 mg dosages were not significant for most endpoints.

3. Safety: Rasagilie was found to be associated with weight loss, vomiting, anorexia, imbalance, headache, dizziness and asthenia. 4. Use of rasagaline as both monotherapy and adjunct therapy is very beneficial to the therapeutic treatments of PD

1. Weintraub, D, Comella, C, Horn, S. Pathophysiologu, Symptoms, Burden, Diagnosis, and Assessment. The American Journal of Managed Care. 2008 Mar; 14 : S40-S48. 2. Rao, S, Hofmann, L, Shakil, A. Parkinsons Diease: Diagnosis and Treatment. American Family Physician. 2006 Dec; 74 : 2046-54 3. Chen, J, Merlin, V, Swope, D. Parkinsons Disease. In: DiPiro JT et al. Pharmacotherapy. 6th ed. New York : McGraw-Hill Medical Publishing, 2005. 977- 988 4. Parkinson Study Group. Archives of Neurololgy. 2002; 59: 1937-1943.

Horstink M, Tolosa E, Bonuccelli U, Deuschl G, Friedman A, Kanovsky P et. Al. Review of the therapeutic management of Parkinson's disease.

Report of a joint task force of the European Federation of Neurological Societies and the Movement Disorder SocietyEuropean Section. Part I: early (uncomplicated) Parkinson's disease. Eur J Neurol. 2006 Nov;13(11):1170-85.
Horstink M, Tolosa E, Bonuccelli U, Deuschl G, Friedman A, Kanovsky P et. Al. Review of the therapeutic management of Parkinson's disease.

Report of a joint task force of the European Federation of Neurological Societies (EFNS) and the Movement Disorder SocietyEuropean Section (MDS-ES). Part II: late (complicated) Parkinson's disease. Eur J Neurol. 2006 Nov;13(11):1186-202.
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