1. Treatment of Parkinson’s Disease Christopher Buchanan CHEM 5398/Buynak April 3, 2007

2. Parkinson’s Disease Overview Prevalence: 0.3% of U.S. Population –Increases to 4-5% for those 85 years old and older Dopaminergic degeneration in the substantia nigra –in the deep gray matter of the brain –Basal ganglia produce less dopamine

3. Parkinson’s Overview (cont’d) Symptoms: –Bradykinesia (slowed movements) –Resting tremor –Rigidity Other Neurotransmitters are affected –Non-Adrenergic, Serotinergic, and Cholinergic neurons are lost –Results in: cognitive decline, sleep abnormalities, depression, gastrointestinal and genitourinary problems –Usually Seen in Later Stages of Parkinson’s

4. Therapy Therapy should begin when normal functions are impaired to due to symptoms (i.e. limits daily activities) –Therapy must be individualized based on progression and time of onset Therapies vary depending on age of onset, progression of symptoms, and side-effects of drugs

5. Medicinal Therapy Levadopa (L-DOPA) –Still the preferred medication to control Motor symptoms –Used in combination with Carbidopa to prevent premature decarboxylation Drug: Sinemet

6. L-DOPA -Adapted from Presentation Slide from Dr. John Buynak Levodopa is decarboxylated to form dopamine, thus replenishing the dimished supply Dopa Decarboxylase is saturated at 70 to 100 mg/day

7. L-DOPA Downsides –Continual use can lead to motor complications (dyskinesia), which must be treated –This can be somewhat offset by lowering the dosage This is an important factor for patients with Early Onset Parkinson’s Disease

8. Dopamine Agonists Directly stimulate dopamine receptors Bromocriptine (Perlodel) Pergolide (Permax) wikipedia http://en..org/wiki/Parl odel http://en.wikipedia.org/wiki/Pergolide

9. Dopamine Agonists Often used in combination with Levadopa Studies have shown that its use alone delays or lowers the incidence of motor complications associated with the use of Levadopa Often prescribed to patients with mild disease at a younger onset age

10. Late Stage Parkinson’s Seen in 40% of Patients having received Levadopa treatment for 5+ years –Motor complications usually arise Patients experience a “wearing off” effect –Each dose of levadopa has a shorter duration of effect Motor Complications treated with: –Dopamine Agonists, MAO-B Inhibitors, COMT Inhibitors

11. MAO-B Inhibitors MAO = monoamine oxidase -Oxidative deamination Reduce disability and delay need for Levadopa –Believed to be somewhat neuroprotective H R-C-NH 2 + O 2 + H 2 O → R-C=O + NH 3 + H 2 O 2 H

12. MAO-B Inhibitors Selegiline (Eldepryl) Rasagiline (Azilect) http://en.wikipedia.org/wiki/Selegiline http://en.wikipedia.org/wiki/Rasagiline

13. COMT Inhibitors COMT: catechol O-methyltransferase Inhibition increases the half life of Levadopa --> decreases “Off” times Tolcapone (Tasmar): Monitored closely due to rare side effect of fatal hepatotoxicity http://en.wikipedia.org/wiki/Tolcapone

14. COMT & MAO Inhibitors http://en.wikipedia.org/wiki/Image:Dopamine_degradation.svg

15. New Therapeutic Approaches Glial Cell-line-Derived Neurotrophic Factor (GDNF) –Shown to aid degenerating neurons –However, there is very little evidence to support it’s widespread use Adenosine Antagonists –Colocalized with striatal dopamine (D2) receptors –Studies show that they often reverse motor defects from Parkinson’s

16. Novel Approaches N-methyl-D-Aspartate (NMDA) Receptor Antagonists –Shown to reduce motor complications from L-DOPA therapy –Amantadine (Symmetrel): http://en.wikipedia.org/wiki/Amantadine

17. Surgical Therapies Deep Brain Stimulation –With precise brain mapping, stimulation of the subthalamic nucleus can be performed –Improves motor function –Reduces dyskinesia and need for medications –Downfall: often causes destructive lesions

18. Interesting Observations An inverse relationship between smoking and Parkinson’s has been demonstrated –Mechanism of protection (if any) is unknown Consuming Caffeine (an adenosine antagonist) has been linked with a lesser risk of developing Parkinson’s

19. Sources Figures: Wikipedia.org Schapira, Anthony H., Bezard, Erwan, et. al “Novel Pharmacological targets for the treatment of Parkinson’s Disease.” Nature Reviews: Drug Discovery. 5 (2006): 845- 854. Rao, Shobha A., Hoffman, Laura A., and Shakil, Amer. “Parkinson’s Disease: Diagnosis and Treatment.” American Family Physician. 74 (2006): 2046-2054 Jankovic, Joseph. “An Update on the Treatment of Parkinson’s Disease.” Mount Sinai Journal of Medicine. 73 (2006): 682-689