The artificial sweetener Aspartame is a dipeptide (phylalanine/aspartic acid) & is found in many (6000?) foods.
PKU is fairly rare (1/15,000)
PD involves a selective degeneration of the nigrastriatal pathway. Transplantation of somas into the striatum produces limited improvements.
Carlsson found that L-DOPA (iv) could very quickly reverse the profound sedation caused by reserpine. This would was completed in the 1950s when: 1) people still believed neurocommunication was exclusively electrical and 2) dopamine was just a precursor to norepinephrine.
Peripheral dopamine acting on the brainstem (area postrema) causes nausea,vommitting, anorexia.
George Cotzias, MD, a Greek clinician scientist working at Brookhaven National Labs, gradually titrated the oral L-DOPA dose. Motor ratings (tremor: ++++ prevents use of limb, + barely perceptible) were made. Note response on an individual level! 13/28 patients were able to go from inpatient to outpatient & return to work! Side-effects included nausea/vomiting/anorexia & anxiety.
L-DOPA has to compete with other amino acids on the large neutral amino acid transporter to pass the Blood Brain Barrier. This can be overcome by taking the pills on an empty stomach. A larger concern is that the effects of L-DOPA wear off and that L-DOPA causes dyskinesias, involuntary movements of the head, trunk, upper & lower extremities.
Selegiline (se-LE-ji-leen) isMAOBselective at moderate doses. Adverse effects of selegiline are minimal but may include insomnia (especially if taken at bedtime), hallucinations, & jitteriness. The benefits of selegiline are modest with upto 1 hour longer of “on time”. The breakdown products include methamphetamine and amphetamine. Interestingly, Selegiline is a controlled substance in Japan (but not U.S.).Rasagiline produces side effects at rates equivalent to placebo.Hepatoxicity is a rare but serious effect of Tolcapone.Entacaponeɛntəkəˈpoʊn/has a very short half-life which results in many (8x) doses/day.
Dopamine breakdown results in the formation of free radicals like hydrogen peroxide which have an unpaired electron. The formation of these free radicals can result in tissue damage specifically to DNA, proteins, & lipids.
Arm 1 received L-DOPA (dose increased from 62.5 mg, tid) & benserazide, a peripheral AACD inhibitor not approved for use in the U.S.Arm 2 received selegiline (5 mg once per day for once week, then twice per day).An extension of the Webster score is described at: http://www.dwp.gov.uk/publications/specialist-guides/medical-conditions/a-z-of-medical-conditions/parkinsons-disease/rating-scale-pd.shtml
Note that an appreciable portion of both groups did not complete the study (arm 1 lost 51.8%, arm 2: 45.4%).On 31 March 2005 following a urinary tract infection,Pope John Paul II developed septic shock, a form of infection with a high fever and low blood pressure. Interestingly, the miracle that made him a saint was Sister Marie Simon-Pierre had lasting relief from her PD following a prayer to John Paul II.
Bromocriptine is an older agent that is not used very much. Ratings of motor behavior were made. These findings show that MPTP does not cause dyskinesia, only MPTP & L-DOPA.
Sleep attack refers to strong desire to quickly goto sleep. This has resulted in some car accidents. This has occurred in patients with clean driving records and was verified by passengers. This resembles narcolepsy.Apomorphine is used during the “off” periods in patients with variable response to L-DOPA. Apomorphine has high affinity for D4 and moderate affinity for D2, D3, D5 and adrenergic alpha 1D, 2B, & 2C receptors. Apomorphine & ondansetron can result in profound hypotension. This combination is contraindicated.
Extreme changes in behavior have been documented by chart-review to occur in about 5% of dopamine agonist patients. The true # may be as high as 20%. This reported noted 7/28 or 18.4%.After 3 years of parkinsonism, a 46-year-old married man was diagnosed as having PD, and ropinirolemonotherapy was initiated, with the dosage gradually increased to 15 mg/d. He subsequently developed “excessive libido” that “occasionally causes arguments with my wife.” Later carbidopa/levodopa was added, and the hypersexuality persisted for the next 2 years, with the patient or wife mentioning this to physicians at least 2 other times. Ultimately, with the hypersexuality “becoming a marital issue,” the dose of ropinirole was tapered and replaced with entacapone (COMT inhibitor), leading to reduction of problematic libido. A 49-year-old married man with an 8-year history of PD developed a compulsive gambling habit a month after increasing his ropinirole dosage from 15 to 21 mg/d. Initially regarded as a psychiatric problem, the compulsive gambling was managed with counseling and attendance at Gamblers Anonymous meetings, which controlled the urge but did not eliminate it. A year later, his wife told the neurologist that he had “an excessive sex urge,” later necessitating a call to the police after her husband chased her when she refused sex. Other new-onset compulsions included intense focus on his hobby of making stained glass windows, often staying up all night to work on these. His appetite and alcohol intake also increased. Quetiapine (atypical antipsychotic) was initiated at dosages up to 300 mg/d without effect on his sexual demands. He was diagnosed as having bipolar disorder, and his medical regimen was switched from quetiapine to carbamazepine (anticonvulsant)without benefit. Not until the dosage of ropinirole (then 24 mg/d) was tapered and carbidopa/levodopa substituted did his pathologic behaviors remit, with his wife reporting a “complete transformation” with the levodopa and entacapone. “I have my husband back,” she said. “It was like I was married to an alien.”
Bromocriptine very strongly binds to D2 and strongly binds to D3 & D4 receptors. There were approximately 250 participants/group at start of trial.Percent Not Completing Studybromocriptine: 68.8% versus less than half-that for other groups!
Pronunciation:trye hex ee fen' idilThe reason that muscarinic antagonists are useful for symptom management is unclear but they have been used for decades. Tryhexyphenidyl targets M1. Because of potential confusion, these may not be the best agents for use with very old/Alzheimer’s patients.
An example of relative risk is if 20 smokers/100 developed a disease versus 1 non-smoker/100 or .20/.01 = RR of 20. See also: http://en.wikipedia.org/wiki/Relative_risk
Piscicide is used to kill fish. Rotenone is also found in some plants so may be used in “organic” foods. Rotenone is used for fish management.Paraquat can be used to generate free radicals in the laboratory, especially superoxide (O2-)A case-control study of farm workers in North Carolina & Iowa revealed elevated PD with rotenone (OR =2.5) & also paraquat (OR = 2.5)
Pharmacotherapies for parkinsons disease
Pharmacotherapies for Parkinson’s Disease Brian J. Piper, Ph.D., M.S.
Objectives• Describe biosynthesis and elimination of dopamine & the importance for PD symptom management.• Outline the rationale (pros & cons) for different secondary treatments of PD including MAOB-I, & DA agonists.
Disease Frequency in US Genetic Patho- Neuro Pharm Goal Effectiveness physiology chem ManagementParkinson’s 500 K low nigra- DA common sym high striatalAlzheimer’s 5.4 million moderate diffuse ACh? common sym slight cortexHuntington’s 30 K high striatum ? uncommon sym smallALS 25 K low motor Glut? common sym small neuronsACh: acetylcholine; DA: dopamine; Glu: glutamine; sym: symptom management
Ideopathic Parkinson’s Disease• Neurodegenerative disease characterized by: – resting tremor – rigidity – bradykinesia – a + response to PD pharmacotherapy• Prevalence ≈ 1 million• Risk Factors – rural > urban – age: > 65 1%; > 80 2.5% – sex: 2 M : 1 F Pill rolling (20 sec): http://www.youtube.com/watch?v=0-t4RTQ0EsM Parkinson’s Symptoms (1st min only): http://www.youtube.com/watch?v=_L_WF6gv5BI .Van Den Eeden et al. (2003). Am J Epidemiology, 157, 1015-1022 Chen et al. (2007). Parkinson’s Disease. In DiPiro Pharmacotherapy.
History of L-3,4-dihydroxyphenylalanine (1950s) • L-DOPA (B) used to counteract reserpine (A) • This effect corresponded with dopamine levels in the brain Arvid Carlsson, MDCarlsson (2001). Science, 294, 1021-1024. 1923 -
History of L-3,4-dihydroxyphenylalanine (1960s)• Additional of a peripheral AADC inhibitor improved response and limited nausea
History of L-3,4-dihydroxyphenylalanine (1960s) • Additional of a peripheral AADC inhibitor improved response and limited nauseaOn versus Off L-DOPA: http://www.youtube.com/watch?v=sf1N0Zf5IqA
Limitations of carbidopa/levodopa (1970s) • competition with other proteins to cross BBB • “unawakening” • dyskinesias occur in majorityExtreme example (1 min): http://www.youtube.com/watch?v=d1jJyk_poqE
Solution #1: Monoamine OxidaseB Inhibition • MAO is localized presynaptically & extrasynaptically (glia) • MAO-A: preferentially deaminates – Dopamine & norepinephrine – 5-HT & melatonin • MAO-B: preferentially deaminates – dopamine & phenethylamine • Target of older class of antidepressant drugs (1957-1970)Acronyms:DOPAC: 3,4-dihydoxyphenylacetic acidAD: aldehyde dehydrogenaseHVA: homovanillic acid
Solution #2: COMT Inhibition• catechol-O-methyl transferase is found centrally & peripherally COMT: catechol-O-methyl transferase 3-O-MD: 3-O-methyl DOPA 3MT: 3-methoxyltyramine
Selegiline Rasagiline Tolcapone Entacapone (L-deprenyl) (azilect) (tasmar) (comtan) mechanism MAOB MAOB peripheral peripheral (irreversible) COMT COMT central COMT monotherapy yes yes no no other meth & amph hepatoxicity 0.5 hour metabolites; half-life insomnia hallucinationsChen et al. (2008). Parkinson’s disease. In DiPiro’s Pharmacotherapy.
Slowing of Further Neurodegeneration?• PD may occur by – DA induced formation of free radicals (H2O2) – apoptosis• MAOB inhibition may act to prevent these mechanisms but this is difficult to establish clinically
PD Progression • Early PD patients (N=520) were randomized to arm 1 (L-DOPA & AADC inhibitor) or arm 2 (selegiline, L-DOPA, AADC inhibitor). • Webster score, conducted non-blind) includes motor function (hand- bradykinesia, face, speech, flexibility, rising from chair, balance).Parkinson’s Disease Research Group British Medical Journal, 307, 469-472.
PD Progression • Early PD patients (N=520) were randomized to arm 1 (L-DOPA & AADC inhibitor) or arm 2 (selegiline, L-DOPA, AADC inhibitor). • Mortality from a variety of causes were also recorded. 2.8% for Arm 1 & 9.6% for Arm 2. 1920 - 2005Parkinson’s Disease Research Group British Medical Journal, 307, 469-472.
Thanks, home chemists!W. Langston, M.D. • Barry Kidston develops Parkinson’s after synthesizing MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) • Later cases were described as: – “Three of the four patients were hospitalized with 14 days to 6 weeks of first use of the drug. Examination in each revealed near total immobility, marked generalized increase in tone, a complete inability to speak intelligibly, marked diminution of blinking, fixed stare, constant drooling” – Stopping L-DOPA resulted in “complete immobility & rigidity, being only able to move his eyes” Langston et al. (1983). Science, 219, 979-980.
MPTP= Parkinson’s model Immunocytochemistry for tyrosine hydroxylase in rhesus monkeysParkinson’s Disease Normal Masilamoni et al. (2011). Brain, 134, 2057-2073.
Dyskinesia• Marmosets (N=16) received MPTP. One month later: – Control – ropinirole (D23 agonist) – bromocriptine (D234 agonist) – L-DOPAPierce et al. (1996). British Journal of Pharmacology, 118, 37P.
Compulsive Behaviors with Dopamine23 Agonists • sexual • gambling • other repetitive behaviorsBostwick et al. (2009). Mayo Clinic Proceedings, 84(4), 310-316.3 min: http://www.youtube.com/watch?v=3oNkYNVdsio
PD Progression with D agonist benserazide: peripheral DOPA decarboxylase inhibitor bromocriptine: D234 agonistRang et al. (2007). Pharmacology. p. 519.
Muscarinic Antagonists• Trihexyphenidyl (Artane) and Benztropine (Cogentin)• Rationale – Muscarinic Receptors on striatal neurons mediate cholinergic tremor – May cause presynaptic inhibition of dopamine release• Adverse effects – “atropine-like”: dry mouth, inability to sweat, impaired vision, urinary retention, constipation, drowsiness, confusion
Summary Pro Con L-DOPA awakening unawakening dyskinesia MAOB-I delay time until L- long-term DOPA outcomes* dopamine agonists reduced dyskinesia compulsions sleep attack*needs additional study
Caffeine & Decreased PD Risk • Dietary habits were obtained from middle aged men (N=8,000) in 1965. • Subjects were monitored for 30 years for incidence of PD. • Mechanisms – 3rd variable – antioxidantRoss, G. W. et al. (2000). JAMA, 283, 2674-2679.
Smoking & Decreased PD Risk • A meta-analysis of 44 studies (6,814 cases, 11,791 controls) has revealed a highly consistent reduction. • Current smokers are 60% less likely to develop PD than non-smokers. • Ex-smokers are 40% less likely to develop PD than non-smokers • Potential mechanisms – third variable? – ↑ dopamine – Inhibition of MAOB Relative Risk = Probability Exposed Probability UnexposedHernan (2002). Annals of Neurology, 52, 276-284.
Pesticides & Increased PD Risk • origin of rural > urban for PD is unclear • Rotenone is an insecticide & piscicide and causes MPTP like neurodegeneration (animals) • Paraquat is one of the most common herbicides in the world.Tanner et al. (2011). Environmental Health Perspectives, 119, 866-872.
Terminology Refresher bradykinesia: slowed movement dyskinesia: involuntary movement involving head, neck, or upper extremeties dystonia: abnormal tone of any tissue, sustained muscle contractionsPronunciation: http://dictionary.reference.com/browse/dyskinesia?s=thttp://dictionary.reference.com/browse/idiopathic