Novità terapeutiche nel morbo di Parkinson. Giuseppe Bellelli - PDF

Novità terapeutiche nel morbo di Parkinson Giuseppe Bellelli The history of PD treatment 1817, James Parkinson provided the first detailed description in his monography An essay on the Shaking Palsy 1960,

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Novità terapeutiche nel morbo di Parkinson Giuseppe Bellelli The history of PD treatment 1817, James Parkinson provided the first detailed description in his monography An essay on the Shaking Palsy 1960, Ehringer discovered dopamine deficiency in corpus striatum and SN 1961, Hornykiewicz & Birkmayer and the antiparkinsonian effect of L- Dopa 1967, Cotzias et al. efficacy of oral L-dopa for the treatment of chronic Parkinsonism New pharmacologic horizons in the treatment of Parkinson disease Parkinsons disease (PD) is a progressive neurodegenerative condition characterized by resting tremor, bradykinesia, rigidity and postural instability as result of loss of dopaminergic neurons in the substantia nigra pars compact (SN pc; area A-9) As the disease progresses, neuron degeneration continues, involving other systems, including mesocortical dompaminergic cells (area A-10), noradrenergic (locus coeruleus), serotoninergic (dorsal raphe nuclei), cholinergic (nucleus basalis of Meynert), histaminergic, and peptidergic systems Bonuccelli U et al, Neurology 2006 New pharmacologic horizons in the treatment of Parkinson disease According to the staging proposed by Braak et al, at first pathology is confined to the medulla (dorsal motor nucleus of the vagus and intermediate reticular region of the medulla). SN degeneration represents an intermediate stage Later there is involvement of the forebrain and ultimately of the neocortex. Widespread multisystem nature of the neurodegenerative process of PD and explains the appearance of new motor (gait disturbances, disequilibrium, falls, camptocormia, swallowing, and speech difficulties) and non motor (autonomic dysfunction, sleep disorders, pain, depression, dementia) symptoms that are only partially responsive to or nonresponsive to dopaminergic treatment Bonuccelli U et al, Neurology 2006 Sommario Motor symptoms Neuroprotective agents Symptomatic therapy DBS Rehabilitation Non motor symptoms Depression Cognitive deficits Potential neuroprotective drugs (CINAPS) Caffeine Coenzyme Q 10 Creatine Estrogen GPI 1485 GM-1 ganglioside Mynocycline Nicotine Pramipexole Ropinirole Rasagiline Selegiline Adenosine antagonist Antioxidant/mitochondrial enhancer Mitochondrial enhancer Undetermined /multiple Trophic factor Trophic factor Anti-inflammatory/anti-apoptotic Unknown Antioxidant/vesicular trafficking Antioxidant Antioxidant/anti-apoptotic Antioxidant/anti-apoptotic PD Neuroprotection: Vitamin E and Selegiline DATATOP trial (1993) Randomized, double-blind, prospective 800 patients randomized to a dose of 2,000 IU of vitamin E/day or placebo Followed for 14 ± 6 months Primary endpoint: onset of disability requiring use of levodopa No difference between tocopherol and placebo groups in the average time to required levodopa (hazard ratio 0.91, 95% CI.74 to 1.12) Selegiline was able to delay the requirement for levodopa by 9 months compared to placebo (symptomatic effect?) AAN 2007 PD Neuroprotection: Rasagiline Irreversible and selective MAO- B inhibitor with a 5-10 greater potency than selegiline Delayed-started trial to assess the neuroprotective effect of rasagiline 371 subjects treated with rasagiline 2 and 1 mg/day for 12 months showed better UPDRS score than subjects whose treatment was delayed for 6 months (P=.001 and P=.005, respectively) Inconclusive results Parkinson Study Group 2004, NEJM Effects of Coenzyme Q 10 in Early Parkinson Disease Conclusions: Coenzyme Q 10 was safe and well tolerated at dosages up to 1200 mg/d. less disability developed in subjects assigned to Coenzyme Q 10 than in those assigned to placebo, and the benefit was greatest in those receiving the highest dosage. Coenzyme Q 10 appears to slow the progressive deterioration of function in PD but these results needs to be confirmed in a larger study Arch Neurol 2002; 59: Recommendations for Neuroprotection There is insufficient evidence for neuroprotection (Level U): Amantadine Ropinirole Pramipexole NMDA receptor antagonist Riluzole AAN, 2007 Symptomatic treatment of motor symptoms of PD The efficacy of L-dopa is unsurpassed Double-blinded, RCT 361 PD patients to placebo or L-dopa (150mg/day, 300 mg/day, or 600 mg/day) Primary outcome: masked assessment of change in UPDRS from baseline after 40 weeks of treatment and 2-week washout Patients randomized to all L-Dopa doses: significantly better UPDRS scores than patients on placebo Highest doses greatest benefit Parkinson Study Group 2004, NEJM. PSG NEJM 2004; 351: L-Dopa è più efficace dal punto di vista sintomatologico rispetto ai dopaminoagonisti (CALM-PD study) Improvement with levodopa: Improvement Change in UPDRS score Pramipexole L-dopa p= Time (months) 5.9 points vs pramipexole (p=0.003) on total UPDRS at 4 years 4.48 points vs ropinirole (p=0.008) on UPDRS motor subscale at 5 years 2.9 points vs cabergoline (p 0.001) on UPDRS motor subscale at 5 years Holloway et al, Arch Neur 2004 Il trattamento con L-dopa ha significativamente ridotto la mortalità associata al PD dal 1960 ad oggi 100 Patients with severe disability and death (%) Untreated patients L-dopa treated patients Years since diagnosis Hoehn and Yahr, 1967; Hoehn, 1983 I problemi connessi all uso di L-Dopa L-Dopa è tossica? L-Dopa accellera la perdita dei neuroni dopaminergici? L-Dopa favorisce la comparsa di fluttuazioni motorie e disciniesie? Problemi associati con il rilascio pulsatile di L-Dopa Dyskinesias are related to L- dopa use? Chronic L-dopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions Murer, et. al. Ann Neurol 1998; 43: ELLDOPA study La risposta a L-Dopa varia con il progredire della patologia Clinical effect On Off Clinical effect Clinical effect Levodopa Levodopa Levodopa Time (hours) Early disease Smooth, long duration of clinical benefit Low incidence of dyskinesias Mid-stage disease Diminished duration of clinical benefit Increased incidence of dyskinesias Advanced disease Clinical response mirrors levodopa plasma pharmacokinetic profile On time is associated with dyskinesias Dyskinesia threshold Response threshold Obeso et al, Neurology 2000 Meccanismi che determinano l insorgenza di complicanze motorie Progressione malattia La degenerazione progressiva dei neuroni dopaminergici determina una riduzione delle capacità di storage dopaminergico nello striato Fluttuazione dei livelli plasmatici di L-Dopa (perdita della capacità di buffer) Stimolazione pulsatile dei recettori domaminergici dello striato Plasma levodopa concentration (ng/ml) Continuous delivery of levodopa by infusion reverses motor complications Time of day Oral levodopa After 6 months levodopa infusion MA L INFUSIONE NON SEMPRE E PRATICABILE p 0.001 Off-time (h/day) p 0.001 Dyskinesia score (AIMS) AIMS=Abnormal Involuntary Movement Score Stocchi et al, 2005 Complicanze motorie nel PD Fluttuazioni motorie End of dose (wearing off) Fluttuazioni motorie imprevedibili (fenomeni on-off) Doses failure Episodi di freezing Discinesie Discinesie di picco dose Discinesie difasiche D-I-D Distonie Olanow et al, 2001 La L-Dopa fobia Insorgenza di discinesie nel PD Le discinesie insorgono approssimativamente nel 50-75% dei pazienti con PD dopo 5-10 anni di trattamento con L-Dopa Rascol et al PSG 2000 Clinical Questions 1. Quali farmaci riducono i fenomeni off e che efficacia hanno? 2. Quali farmaci riducono le discinesie? 3. Il DBS riduce il time off, le discinesie, l uso dei farmaci e migliora la funzione motoria? 4 options + 1 Dopamine agonists MAO B inhibitors COMT inhibitors Sustained release Carbidopa/Levodopa Amantadine Evidence: Dopamine Agonists Author Drug Class N Study Duration Decrease Off time Active Decrease Off time Placebo Olanow Pergolide I 189/ week 32% (1.8 h)* 4% (0.2 h) Lieberman Pramipexole I 181/ week 31%* 7% Guttman Pramipexole II 79/83 40 week 15% (2.5 h)* 3% Rascol Ropinirole II 23/23 12 week 23%* 4% Lieberman Ropinirole II 95/54 26 week 11.7%* 5% Dewey Apomorphine II 20/9 4 week 34% (2 h)* 0% Guttman Bromocriptine II 84/83 40 week 8% 3% Steiger Cabergoline III 19/10 24 week 40% (2 h)* 18% (0.7 h) Ahlskog Cabergoline III 17/10 24 week 59% (3.3 h)* NS AAN, 2007 Evidence: MAO B Inhibitors Author Drug Class N Study Duration Decrease Off time Active Decrease Off time Placebo PSG PSG Rascol Waters Rasagiline (0.5 mg) I 164/ week 23% (1.4 h)* 15% (0.9 h) Rasagiline (1.0 mg) I 149/ week 29% (1.8 h)* 15% (0.9) Rasagiline (1.0 mg) I 231/ week 21% (1.2 h)* 7% (0.4 h) Orally Disintegrat Selegiline II 94/46 12 week 32% (2.2 h)* 9% (0.6 h) Golbe Selegiline III 50/46 6 week NR NR AAN, 2007 Evidence: COMT Inhibitors Author Drug Class N Study Duration Decrease Off time Active Decrease Off time Placebo PSG Entacapone I 103/ week NR NR Rascol Entacapone I 227/ week 21% (1.2 h)* 7% (0.4 h) Poewe Entacapone II 197/ week 25.8% (1.6 h)* 13.4% (0.9 h) Rinne Entacapone II 85/86 24 week 23.6% (1.3 h)* 1.9% (0.1 h) Fenelon Entacapone II 99/63 12 week 0.9 h 0.4 h Rajput Rajput Baas Baas Tolcapone (100 mg tid) II 69/66 12 week 32% (2.3 h) 20% (1.4 h) Tolcapone (200 mg tid) II 67/66 12 week 48% (3.2 h)* 20% (1.4 h) Tolcapone (100 mg tid) II 60/58 12 week 31.5%* 11% Tolcapone (200 mg tid) II 59/58 12 week 26.20% 11% AAN, 2006 Evidence: Sustained Release Carbidopa/Levodopa Author Drug Class N Jankovic Hutton Study Duration Decrease Off time Carbidopa/levodopa CR/IR III week NS Carbidopa/levodopa CR/IR III week NS Ahlskog Lieberman Carbidopa/levodopa CR/IR III week NS Carbidopa/levodopa CR/IR III week NS Recommendations for Patients with PD and Motor Fluctuations Entacapone and rasagiline should be offered to reduce off time in PD patients (Level A)* Pergolide, pramipexole, ropinirole, and tolcapone should be considered to reduce off time (Level B)* Tolcapone (hepatotoxicity) and pergolide (valvular fibrosis) should be used with caution and require monitoring Apomorphine, cabergoline, and selegiline may be considered to reduce off time (Level C)* Sustained release carbidopa/levodopa and bromocriptine may be disregarded to reduce off time (Level C)* *Strength indicates level of supporting evidence, not hierarchy of efficacy AAN, 2007 Relative Efficacy of Medications in Reducing Off Time Rasagiline similar to entacapone Bromocriptine similar to pramipexole Tolcapone similar to pergolide Cabergoline similar to bromocriptine Tolcapone similar to entacapone Ropinirole possibly superior to bromocriptine Many of these studies not powered to demonstrate superiority of one drug over another Other than comparisons of ropinirole and bromocriptine, there is insufficient evidence to conclude which one agent is superior to another in reducing off time Recommendations for Medications that Reduce Dyskinesia Amantadine may be considered for PD patients with motor fluctuations to reduce dyskinesia (Level C) Insufficient evidence to support or refute the efficacy of clozapine in reducing dyskinesia (Level U) Conclusions: Nanoparticular CoQ10 at a dosage of 300 mg/d is safe and well tolerated and leads to plasma levels similar to 1200 mg/d of standard formulations. Add-on CoQ10 does not display symptomatic effects in midstage Parkinson disease. Arch Neurol. 2007;64(7): Conclusions: Transdermal rotigotine significantly improved off time in subjects with Parkinson disease not optimally controlled with levodopa and was safe and well tolerated, with typical dopaminergic side effects and occasional application site reactions. Neurology 2007 Il problema: molti pazienti richiedono levodopa per il controllo dei sintomi Need for l-dopa in patients initiated with dopamine agonist (pramipexole) Need for l-dopa in patients initiated with monoamine oxidase inhibitor (selegiline) % patients requiring supplemental levodopa % 46% 23% 16% Years after randomization Probability of requiring levodopa therapy (%) Months after randomization PSG, 1997; Holloway et al, 2004 I preparati combinati L-Dopa + entacapone enhances the pharmacokinetics of levodopa 2.5 Plasma levodopa (µg/ml) Traditional levodopa L-Dopa entacapone Time by which the half-life of l-dopa is extended Time (h) Ruottinen and Rinne, 1996 L-Dopa & entacapone: impatto sulle ADL 14 L-Dopa entacapone/lce Traditional levodopa plus placebo UPDRS-s ADL score Time (months) Poewe et al, Acta Neurol Scand, 2002 Deep Brain Stimulation Samii A et al, THE LANCET 2004 Evidence DBS DBS of the STN may be considered as a treatment option in PD patients to improve motor function and to reduce motor fluctuatins, dyskinesia, and medication usage (Level C). Patients need to be counseled regarding the risks and the benefits of this procedure. There is insufficient evidence to make any recommendations about the effectiveness of DBS of the GPi or VIM nucleus of the thalamus in reducing motor complications or medication usage, or in improving motor function in PD patients (Level U). Practice Parameter: Treatment of PD with motor fluctuations and dyskinesia (an evidence-based review) Neurology 2006 Exercise treatment & rehabilitation Exercise Therapy in PD Author Cohort size Outcome variable Treatment Duration Wade et al 2003 Marchese et al 2000 Miyai et al PDQ-39, SC-36, peg test, walking multidisciplinar y rehab vs. placebo 20 UPDRS cued vs. noncued exercises 10 UPDRS, ambulation BWSTT vs. physiotherapy 1 x per week x 6 weeks, FU 48 weeks 3 x per week x 6 weeks, FU 12 weeks 3 x per week x 4 weeks, FU 8 weeks Exercise Therapy in PD Author Cohort size Outcome variable Treatment Duration Miyai et al 2002 Hirsch et al 2003 Pachetti et al 2000 Comella et al UPDRS, ambulation BWSTT vs. physiotherapy 18 balance, falls, strength Balance/resista nce vs. balance 32 UPDRS, PDQualif Music therapy vs. physical therapy 18 UPDRS, depression General exercise vs. placebo 3 x per week x 4 weeks, FU 6 months 3 x per week x 10 weeks, FU 14 weeks 1 x per week x 3 months, FU 5 months 3 x per week x 1 month, FU 12 months Recommendation for Exercise Therapy in PD Exercise therapy may be considered to improve function (Level C) Results in improvement in UPDRS Decrease in falls No specific exercise program shown to be superior to another Benefit not sustained after exercise is discontinued Possibili ragioni della ridotta provata efficacia della riabilitazione nel PD Eterogeneità della popolazione (durata e garvità malattia) Misure di outcomes variabili Intervento adattativo Intervento sulla plasticità neuronale Qualità della vita Collaborazione del paziente /interventi educativi (non sempre valutati) Non motor symptoms I sintomi non motori sono spesso il primo segno di wearing off In addition to the motor-related symptoms of PD, nonmotor complications can also be a significant burden for patients. Many of these symptoms are associated with PD itself; however, recent evidence suggests that non-motor symptoms such as anxiety, tingling, coldness of limbs and unclear thinking may frequently occur before motor symptoms emerge, highlighting the importance of their recognition in clinical practice. Isaacson Mov Disord 2005; 20: S52 Background Prospective survey n=99 (Shulman et al., 2001) 88% had at least one of Anxiety, depression, sensory disturbance, fatigue, pain, or sleep disturbance 11% had 5 or more Low physician recognition of nonmotor features in PD Many PD symptoms overlap with features of depression and dementia Validated criteria for depression, psychosis and dementia in PD do not exist AAN, 2007 Evidence: pharmachological treatment of depression in PD Amitriptyline may be considered for depression associated with PD (Level C) Not necessarily the first choice for treatment Citalopram and sertraline (no benefit underpowered) Insufficient evidence to make recommendations for other pharmacologic depression treatments in PD (Level U) Recommendations for Psychosis Treatment For patients with PD and psychosis Clozapine should be considered (Level B) Associated with agranulocytosis that may be fatal Absolute neutrophil count must be monitored Monitoring requirements may vary by country Quetiapine may be considered (Level C) Olanzapine should not be routinely considered (Level B) Worsens motor function Conclusioni IL PD è una sindrome più che una malattia e deve dunque essere trattata farmacologicamente di conseguenza Non vi sono attualmente preparati che svolgano una provata azione neuronoprotettiva La L-Dopa è il più potente agente antiparkinsoniano ancora in uso ma è gravato da alcuni problemi I farmaci dopaminoagonisti, I-MAO e COMT sono efficaci per le complicanze del PD (fluttuazioni) DBS efficacia limitata ed in casi selezionati Riabilitazione?
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