ParkinsonRasagilina
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Una revisión de la historia natural de la enfermedad de Parkinson, y el rol de rasagilina, un inhibidor de la monoamino-oxidasa B en las disitintas etapas de la enfermedad de Parkinson.
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ParkinsonRasagilina
- 1. Rol de Rasagilina en las etapas evolutivas de la enfermedad de Parkinson Jornada de Actualización en el tratamiento de la enfermedad de Parkinson 24 de Junio de 2015, Arequipa-Perú Nilton Custodio Instituto Peruano de Neurociencias ncustodio@ipn.pe
- 2. Declaración de conflictos de interés • EXPOSITOR CONTRATADO: – Laboratorios Teva, Novartis, Janssen-Cilag, Boehringer-Ingelheim, Lilly, Farmindustria, Tecnofarma, Roemmers. • INVESTIGADOR POR CONTRATO: – Laboratorio Novartis-Suiza, Pfizer-USA, Merck-Sharp-Dohme-USA, Medivation-USA, Newron/Zambon-Italia, Biogen-USA, Roche-USA. • INVESTIGADOR INDEPENDIENTE: – Instituto Peruano de Neurociencias – Universidad de Pensilvania – Instituto Nacional de Ciencias Neurológicas – Clínica Internacional
- 3. Agenda • Historia natural de la enfermedad de Parkinson. • Estrategias de tratamiento farmacológico en EP. • Diseños metodológicos en modificación de la evolución de EP. • Rasagilina en enfermedad de Parkinson inicial. • Rasagilina en enfermedad de Parkinson moderado-avanzado. • Perfil de seguridad y alertas con Rasagilina.
- 4. Agenda • Historia natural de la enfermedad de Parkinson. • Estrategias de tratamiento farmacológico en EP. • Diseños metodológicos en modificación de la evolución de EP. • Rasagilina en enfermedad de Parkinson inicial. • Rasagilina en enfermedad de Parkinson moderado-avanzado. • Perfil de seguridad y alertas con Rasagilina.
- 5. Estudios epidemiológicos de EP en comunidad de Lau LM & Breteler MM. LancetNeurol 2006;5:525-535. Prevalencia Incidencia 0.3 % Población general 1 % Mayores 60 años edad 0.08 - 0.18 % Población general M/F : 2.6/1
- 6. Los síntomas clásicos de la EP: Fenómenos Motores Enfermedad de Parkinson Temprano • Temblor reposo unilateral • Disminución de balanceo • Pérdida destreza en una mano • Pérdida de expresión facial •Trastorno de la marcha
- 7. Neuropatología de la enfermedad de Parkinson Patología de la Sustancia negra Pérdida neuronal Inclusiones Lewy
- 8. Neuropatología de la enfermedad de Parkinson Patología de la α-sinucleína Sustancia negra Corteza cerebral
- 9. Estadio del depósito de cuerpos de Lewy según Braak Braak H, et al. J Neurology. 2002;249(suppl 3):1432-1459.
- 10. Progresión de síntomas en enfermedad de Parkinson PuntajeUPDRS 2 3 4 5 10 12 14 16 18 20 Unilateral Bilateral Discapacidad Sintomas No Motores Demencia Sintomas No Motores
- 11. PuntajeUPDRS 2 3 4 5 10 12 14 16 18 20 Unilateral Bilateral Discapacidad Sintomas No Motores Demencia Fluctuaciones motoras Discinesias Progresión de síntomas en enfermedad de Parkinson
- 12. Progresión de síntomas no motores en EP Efecto de Medicación Intrínseco a EP PROGRESIÓN DE ENFERMEDAD Y EDAD SDE Ataques Sueño Fluctuaciones no motoras DCI SDD Hipotensión ortostática DCSREM Constipación Urgencia urinaria Disfunción eréctil Depresión Hiposmia Dolor Alucinaciones visulales Demencia Inestabilidad postural/Caída
- 13. Prevalencia de SNM según estadio de EP Modificado de Barone P, et al. Mov Disord 2009;24:1641-49. Porcentaje Precoz (N=107) Tratado estable (N=753) Avanzado (N=212) GastroIntestinal Dolor Urinario Cardiovascular Sueño Fatiga Apatía Atención Memoria Piel Psiquiátrico Respiratorio Miscelánea
- 14. Hipotensión ortostática e incontinencia urinaria correlacionan con edad y duración de EP Correlación con edad y duración de la enfermedad (odds ratio) Síntoma M (N=2076) F (N=1338) Sexoa Edadb Duración de enfermedadb Hipotensión ortostática 10% 11% NS 1.03 (1.02-1.05) 1.02 (1.00-1.05) Incontinencia urinaria 21% 22% NS 1.04 (1.03-1.05) 1.04 (1.02-1.05) Disfunción sexual 30% 8% 0.09 (0.06-0.12) 1.02 (1.01-1.03) NS Disfunción eréctil 50% 1.04 (1.02-1.05) NS Disturbios del sueño 35% 43% 1.42 (1.23-1.64) NS 1.03 (1.02-1.04) aOdds <1 es equivalente a riesgo disminuido para mujeres bIncremento de riesgo por 1 año de edad o duración de enfermedad NS = no-significativo Wullner U. et al. Eur J Neurol 2007;14:1405-8.
- 15. Los SNM no son declarados por los pacientes con EP Chaudhuri KR, et al. Mov Disord 2010;25:704-9. Números Positivo No declarado Constipación Hiper sexualidad Sueños vívidos intensos Evacuación intestinal incompleta Dificultad sexual Somnolencia diurna Mareo Actuar durante el sueño DelusionesHiper salivación
- 16. Agenda • Historia natural de la enfermedad de Parkinson. • Estrategias de tratamiento farmacológico en EP. • Diseños metodológicos en modificación de la evolución de EP. • Rasagilina en enfermedad de Parkinson inicial. • Rasagilina en enfermedad de Parkinson moderado-avanzado. • Perfil de seguridad y alertas con Rasagilina.
- 17. La degeneración progresiva de neuronas dopaminérgicas sólo explica algunos síntomas motores Fase Pre sintomática Inicio Sueño Olfactorio* Humor Autonómico Diagnóstico Síntomas no motores tempranos Síntomas específicos Motor Reducción de neuronas dopaminérgicas en EP %Remanentede NeuronasDopaminérgicas Tiempo (años) No motor *Disfunción olfactoria puede preceder a EP clínico por 4 años. Adaptado de Halperin et al. Neurotherapeutics. 2009;6:128-140. Neuronas Colinérgicas Neuronas NorAdrenérgicas Neuronas Serotoninérgicas
- 18. La degeneración de neuronas dopaminérgicas de locus niger afecta la vía nigro-estriatal Jankovic& Tolosa. Parkinson´s Disease and Movement Disorders 2007
- 19. Modelo clásico del efecto modulador de las neuronas dopaminérgicas en los ganglios basales Olanow CR, et al. Neurology 2009;72:S1-S136.
- 20. Modelo clásico del efecto modulador de las neuronas dopaminérgicas en los ganglios basales Olanow CR, et al. Neurology 2009;72:S1-S136.
- 21. Los ganglios basales están organizados e interactúan de manera más compleja Olanow CR, et al. Neurology 2009;72:S1-S136.
- 22. Proyecciones dopaminérgicas y distribución de receptores de dopamina cerebral Brichta L, et al. Trends Neurosci 2013;36(9):543-554.
- 23. Núcleo del rafe, proyecciones serotoninérgicas y distribución de receptores de serotonina cerebral Brichta L, et al. Trends Neurosci 2013;36(9):543-554.
- 24. Proyecciones nor-adrenérgicas y distribución de receptores nor-adrenérgicos cerebrales Brichta L, et al. Trends Neurosci 2013;36(9):543-554.
- 25. Tratamiento sintomático dopaminérgico de la enfermedad de Parkinson Receptores de Dopamina DA L-DOPA 3-OMD DA Agonistas de Dopamina Inhibidores COMT Carbidopa Inhibidores MAO-B DOPAC DA 3-MT DA DA AADC DA Inhibidores COMT* L-DOPA DADA BHEPeriférico CerebroNeurona *Sólo tolcapone inhibe COMT en cerebro. L-DOPA = levodopa 3-OMD = 3-O-metildopa DA = dopamina AADC = Acido aromatico decarboxilasa DOPAC = Acido dihidroxifenilacetico 3-MT = 3-metoxi-tiramina Selegilina/Rasagilina
- 26. Levodopa es el tratamiento sintomático más eficaz en enfermedad de Parkinson • Es útil en todos los estadios de EP. • Múltiples formas de presentación. • Escasos eventos adversos agudos tolerables. • Complicaciones motoras más frecuentes que con AD. • Eventos adversos crónicos son una limitante. Lewitt P. N Engl J Med 2008;359:2468-76.
- 27. Levodopa ofrece un control sintomático consistente Pramipexole Levodopa/carbidopa; p=0.003 Levodopa/carbidopa vs pramipexole1 –4 –2 0 2 4 12 24 42 CambiosenUPDRStotal –16 –14 –12 –10 –8 –6 6 18 36 48 Tiempo (meses) Mejoría Regimen de tratamiento Mejoría vs Levodopa/IDDC Pramipexole1 5.9 puntos en UPDRS total (p=0.003) a 4 años. Ropinirole2 4.48 puntos en UPDRS motor (p=0.008) a 5 años. Cabergoline3 2.9 puntos en UPDRS motor (p<0.001) a 5 años. Levodopa/IDDC vs agonistas dopamina Mejoría en UPDRS después de 4-5 años 300 1Holloway et al. Arch Neurol 2004;61(7):1044; 2Rascol et al. N Engl J Med 2000;342(20):1484; 3Bracco et al. CNS Drugs 2004;18(11):733
- 28. Levodopa tiene mayor posibilidad de complicaciones motoras a largo plazo (CALM -PD) Corbin A, Koster J. Parkinsinism Relat Disord 2007;13(suppl 2):S106. Tratamiento en monoterapia con pramipexole en EP resulta en una significativa baja tasa de discinesia comparada con levo-dopa Pacientes(%)
- 29. Agenda • Historia natural de la enfermedad de Parkinson. • Estrategias de tratamiento farmacológico en EP. • Diseños metodológicos en modificación de la evolución de EP. • Rasagilina en enfermedad de Parkinson inicial. • Rasagilina en enfermedad de Parkinson moderado-avanzado. • Perfil de seguridad y alertas con Rasagilina.
- 30. Obstáculos para demostrar una adecuada estrategia de neuroprotección en enfermedad de Parkinson • Se desconoce la etiología exacta de EP; por lo tanto desconocemos cuál es el “blanco” preciso. • No existe un modelo animal confiable que refleje la naturaleza progresiva y la etiopatogénesis de EP. • No se ha encontrado un método ideal para determina las dosis óptimas a usar en un ensayo clínico. • No existe un adecuado diseño de ensayo clínico que demuestre confiablemente la eficacia de un agente modificador de la enfermedad.
- 31. Diseños de ensayos ideales para neuroprotección en EP • Demostrar el momento en que se produce la progresión de la enfermedad. • Diseño de lavado/retiro de medicación (Cambios en el grupo no tratado desde el basal hasta la visita final realizada después del retiro de la droga). • Cambios desde la visita basal hasta la visita final en el puntaje UPDRS. • Cambios en neuroimágenes de biomarcadores de función dopaminérgica.
- 32. Levo-dopa altera la historia natural de la enfermedad? ELLDOPA (Levodopa vs Placebo) CambiosenUPDRStotal Semana Basal 2 6 10 14 18 22 26 30 34 38 42 46 – 2 – 4 – 6 – 8 Placebo 150 mg 300 mg 600 mg Retiro de droga de estudio 12 10 8 6 4 2 0 Placebo 150 mg 300 mg 600 mg Parkinson Study Group. N Engl J Med 2004;351:2498-2508
- 33. Eficacia clínica y complicaciones motoras por levo-dopa tras 6 meses de tratamiento, son relacionadas a dosis Placebo N (%) 150mg/d N (%) 300mg/d N (%) 600mg/d N (%) p-Value ENROLADOS 90 92 88 91 Algún evento 33 / 37% 33 / 36% 27 / 31% 37 / 41% 0.5177 Fin de dosis 12 / 13% 15 / 16% 16 / 18% 27 / 30% 0.0596 Discinesia 3 / 3% 3 / 3% 2 / 2% 15 / 16% 0.0001 On-off 3 / 3% 1 / 1% 0 / 0% 3 / 3% 0.2602 Distonía 19 / 21% 19 / 21% 14 / 16% 12 / 13% 0.3001 Congelamiento 13 / 14% 9 / 10% 6 / 7% 5 / 5% 0.1497 Parkinson Study Group. N Engl J Med 2004;351:2498-2508 Estudio ELLDOPA (Levodopa vs Placebo)
- 34. Whone AL. Ann Neurol 2003;54:93-101 -25 -20 -15 -10 -5 0 Ropinirole Levo-dopa CambiosenRecaptación de18F-dopa(%) -13 -20 Pérdida de neuronas dopaminérgicas estriatales tras 2 años con agonistas dopaminérgicos y levo-dopa
- 35. Cambios en Captación Dopamina Pramipexole vs Levodopa Parkinson Study Group. JAMA 2002;287:1653-1661 Meses de tratamiento Cambiosdesdeelbasal(%) 10 0 -10 -20 -30 Pramipexole Levo-dopa 0 10 20 30 40 50 (39) (35) (33) (39) (36) (32) Pérdida de neuronas dopaminérgicas estriatales tras 4 años con agonistas dopaminérgicos y levo-dopa
- 36. Olanow CW, et al. Neurology 2009;21(suppl 4):S8-S26 Neuroprotección por agonistas dopaminérgicos o neurotoxicidad por levodopa?
- 37. El diseño de inicio retrasado de tratamiento podría demostrar el efecto modificador de la enfermedad Placebo Intervención de inicio precoz Periodo I Inicio Precoz
- 38. El diseño de inicio retrasado de tratamiento podría demostrar el efecto modificador de la enfermedad Efecto Sintomático Periodo II Inicio retrasado Placebo Intervención de inicio precoz Periodo I Inicio Precoz Intervención de inicio retrasado
- 39. El diseño de inicio retrasado de tratamiento podría demostrar el efecto modificador de la enfermedad Placebo Intervención de inicio precoz Periodo I Inicio Precoz Intervención de inicio retrasado Periodo II Inicio retrasado Posible efecto modificador de enfermedad
- 40. Principios del análisis estadístico de ensayos clínicos con drogas de inicio retrasado: Rasagilina Inicio Retrasado (Placebo-Rasagilina) Inicio Precoz (Rasagilina-Rasagilina) Adapted from Olanow et al. Mov Disord. 2008. Semana 7212 36 48 54 60 6624 42 CambiopromedioenUPDRSdesdeelbasal EmpeoramientoMejoría I I. Superioridad de Inicio Precoz vs Placebo (UPDRS semana 12 – 36) III III. No-Inferioridad de Inicio Precoz vs Inicio Retrasado (UPDRS semana 48 – 72) II II. Superioridad de Inicio Precoz vs Inicio Retrasado(UPDRS desde basal hasta semana 72)
- 41. Diseño del estudio ADAGIO Olanow W, et al. Mov Disord 2008;23(15):2194-2201 36 semanas (9 meses) Fase Doble-ciego Tratamiento Activo Semana 36 semanas (9 meses) Fase Doble-ciego controlado con Placebo Placebo 1 mg/día 2 mg/día 1 mg/día Pacientes EP no tratados 2 mg/día 0 4 12 24 36 42 48 54 60 66 72
- 42. El estudio ADAGIO incluyó población con enfermedad de Parkinson en estadios tempranos Olanow W, et al. Mov Disord 2008;23(15):2194-2201 Pacientes randomizados (n) 1,176 Sexo masculino (n, %) 718 (61.1%) Edad, años (media, DS) 62.2 (9.6) Duración EP, meses (media, DS) 4.5 (4.6) Puntaje total UPDRS (media, DS) Motor AVD 20.4 (8.5) 14,2 (6.4) 5.2 (2.8) Puntaje Hoehn & Yahr (media, DS) 1.5 (0.5)
- 43. Rasagilina 1 mg cumple con los 3 principios del diseño de un estudio con tratamiento de inicio retrasado • Diferencia en UPDRS de 1.7 unidades. • 38% de reducción en la tasa de declinación del puntaje de UPDRS. • Refleja sólo 9 meses de tratamiento activo. Olanow W, et al. N Engl J Med 2009;361:1268-1278 El beneficio no sólo puede atribuirse a efectos sintomáticos. Es un falso positivo?
- 44. Rasagilina 2 mg no cumple con los 3 principios del diseño de un estudio con tratamiento de inicio retrasado Olanow W, et al. N Engl J Med 2009;361:1268-1278 No hay evidencia de superioridad en Inicio Precoz vs Inicio Retrasado. Es un falso negativo?
- 45. Agenda • Historia natural de la enfermedad de Parkinson. • Estrategias de tratamiento farmacológico en EP. • Diseños metodológicos en modificación de la evolución de EP. • Rasagilina en enfermedad de Parkinson inicial. • Rasagilina en enfermedad de Parkinson moderado-avanzado. • Perfil de seguridad y alertas con Rasagilina.
- 46. Eficacia de Rasagilina en EP en estadios iniciales: Estudio TEMPO Fase Doble-Ciego Tratamiento Activo Fase Doble-Ciego controlado con Placebo Rasagilina Retrasada 2 mg/día Rasagilina 1 mg/día Rasagilina 1mg/día 6 Meses 6 Meses N=404 Randomización Rasagilina 2 mg/día Rasagilina 2mg/día N=138 A los 6 meses en grupo placebo de Inicio Retrasado, reciben 2mg N=132 N=134 N=124 Placebo X N=124 N=132 Parkinson Study Group. Arch Neurol 2004;61:561-566 Parkinson Study Group. Arch Neurol 2002;59:1937-1943
- 47. Efectos del tratamiento en el UPDRS a los 6 meses Estudio TEMPO (Análisis Primario: Media ajustada ± DS) 0.51 -0.13 4.07 5.0 0.0 1.0 2.0 3.0 4.0 P < 0.0001 Placebo Rasagilina 2 mg Rasagilina 1 mg P < 0.0001 Mejoría Cambiopromediodesdeelbasal enUPDRStotal Parkinson Study Group. Arch Neurol 2002;59:1937-1943
- 48. Análisis Primario: 371 sujetos Tamaño del efecto: Comparando rasagilina 1 mg por 1 año con rasagilina de inicio retrasado fue -1.8 unidades (95% CI, -3.64 to 0.01, *p=0.05), mientras que comparando rasagilina 2 mg por 1 año con rasagilina de inicio retrasado fue -2.3 unidades (95% CI, -4.11 to -0.48, **p=0.01) -2 -1 1 2 3 4 CambiosenUPDRS Rasagilina 1 mg Rasagilina 2 mg Rasagilina 2mg retrasado Semana * Inicio retrasado ** 0 14 20 5284 4226 32 *p=0.05 **p=0.01 EmpeoramientoMejoría Parkinson Study Group. Arch Neurol 2004;61:561-566 Efectos del tratamiento en el UPDRS a los 12 meses Estudio TEMPO
- 49. Casi la mitad de pacientes (121/266) se mantuvieron en monoterapia con rasagilina por 2 años 0 50 100 150 200 250 300 350 400 450 0 1 2 3 4 5 Años de tratamiento con Rasagilina %Pacientesquepermanecenenelestudio Rasagilina, Monoterapia Rasagilina + otra terapia 100% 69% 45% 32% 23% 18% M Lew. Poster EFNS, Septiembre 2005
- 50. Rasagilina permite preservar las actividades de vida diaria en EP en estadios iniciales 0 0.2 0.4 0.6 0.8 1 1.2 1.4 Placebo Rasagilina Parkinson Study Group. Arch Neurol 2002;59:1937-1943 Empeoramiento CambioenUPDRS-ADL Basal P=0.0003 Estudio TEMPO
- 51. Monoterapia de Rasagilina demostró baja incidencia de efectos adversos dopaminérgicos Efectos dopaminérgicos como monoterapia Rasagilina 1 mg/d (n=149) Placebo (n=151) Náuseas 4.0% 7.3% Hipotensión postural 2.7% 4.6% Vómitos 1.3% 0.7% Alucinaciones 1.3% 0.7% Edema periférico 1.3% 2.6% Somnolencia 0.7% 1.3% Goetz CG, et al. Neurology 2006;66:1427-1429
- 52. Agenda • Historia natural de la enfermedad de Parkinson. • Estrategias de tratamiento farmacológico en EP. • Diseños metodológicos en modificación de la evolución de EP. • Rasagilina en enfermedad de Parkinson inicial. • Rasagilina en enfermedad de Parkinson moderado-avanzado. • Perfil de seguridad y alertas con Rasagilina.
- 53. Respuesta a levo-dopa y aparición de complicaciones motoras según evolución de la enfermedad Inicio de tratamiento (EP temprano) Tratamiento a largo plazo (EP avanzado) Tratamiento a mediano plazo Respuesta motora de larga duración. Baja incidencia de discinesias . Respuesta motora de corta duración. Incidencia incrementada de discinesias. Respuesta motora de corta duración. Tiempo “on” asociado con discinesias .
- 54. Rasagilina permite control adicional de síntomas cuando se adiciona a pacientes que sólo usan ADs -4 -3.5 -3 -2.5 -2 -1.5 -1 -0.5 0 Hauser RA, et al. Mov Disord 2014; 29(8):1028-1034. Mejoría Cambiopromediodesdeelbasal enUPDRStotalalas18semanas Placebo Rasagilina 1 mg Estudio ANDANTE P = 0.012 -1.2 -3.6
- 55. Rasagilina redujo el tiempo de “off” por cerca de 2 horas cuando fue adicionado a levo-dopa Parkinson Study Group. Arch Neurol 2005;62:241-248 2 4 6 8 10 12 16 20 2414 18 22 26 0.5 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 Semana Rasagilina 0.5 mg (n=157); p = 0.02 Rasagilina 1 mg (n=142); p < 0.0001 Placebo (n=152) 0 Horasdereducióndeltiempo“off” 0.9 horas 1.4 horas 1.9 horas Tiempo “off” diario total (en horas) fue 6.0 para placebo y rasagilina 0,5 mg/d, y 6.3 para rasagilina 1 mg/d Estudio PRESTO
- 56. Reducción del tiempo “off” con Rasagilina es similar al tiempo “off” producido por Entacapona -1.20-1.18 -0.40 Rasagilina 1 mg Entacapona 200 mg Placebo-LD/DDI -0.2 -0.7 -2.2 -1.2 -1.0 P = 0.0001P < 0.0001 Rascol O, et al. Lancet. 2005; 365:947-954. Todos los pacientes con LD/IDD Mejoría Cambiodesdeelbasalenhoras
- 57. -1.95 -1.78 -1.67 -1.27 -1.05 -0.83 -2.4 -2 -1.6 -1.2 -0.8 -0.4 0 Sin I-COMT (n=307) Con I-COMT (n=165) *p<0.05; ***p<0.001 vs placebo *** * Placebo Rasagilina 0.5 mg/d Rasagilina 1 mg/d Mejoría Cambiodesdeelbasalenhoras Elmer Lawrence & Parkinson Study Group. MDS 2005 Reducción del tiempo “off” con Rasagilina es similar al tiempo “off” producido por Inhibidores COMT Todos los pacientes con LD/CD
- 58. -1.89 -1.75 -0.85 -1.06 -2 -1.6 -1.2 -0.8 -0.4 0 Rasagiline 1.0 mg/d Placebo Sin ADs (n=91) Con ADs (n=217) ***p<0.001 vs placebo *** Reducción del tiempo “off” con Rasagilina es similar al tiempo “off” producido por Agonistas dopaminergicos Elmer Lawrence & Parkinson Study Group. MDS 2005 Mejoría Cambiodesdeelbasalenhoras Todos los pacientes con LD/IDD
- 59. Adicionado a levo-dopa, Rasagilina mejora significativamente las AVDs durante el tiempo “off” -3 -2.5 -2 -1.5 -1 -0.5 0 Rascol O, et al. Lancet. 2005; 365:947-954. Mejoría Cambiopromediodesdeelbasal enUPDRS-ADLalas18semanas Placebo, n=229 Rasagilina 1 mg, n=231 Estudio LARGO P = 0.0001 Todos los pacientes con LD/IDD -0.89 -2.61
- 60. Baja tasa de eventos adversos cognitivos y conductuales cuando rasagilina se adiciona a L-dopa Eventos adversos cognitivos y conductuales en el estudio PRESTO Eventos Adversos cognitivos y conductuales frecuentes Rasagilina 1mg + levodopa (n=149) % pacientes Placebo + levodopa (n=159) % pacientes Desórdenes del sueño/Insomnio 8.1 6.9 Somnolencia 6 4.4 Depresión 4.7 6.3 Alucinaciones 4 3.1 Confusión 1.3 0.6 L Elmer et l. J Neurol Sci 2006;48:78-83
- 61. Razonable evidencia clínica sugieren el uso de Rasagilina en todos las fases de EP Monoterapia Terapia de adición TEMPO ANDANTE PRESTO LARGO Mejoría en UPDRS total Si Si Si Si Reducción del tiempo en “off” -- -- Si Si Aceptable tolerabilidad Si Si Si Si
- 62. Agenda • Historia natural de la enfermedad de Parkinson. • Estrategias de tratamiento farmacológico en EP. • Diseños metodológicos en modificación de la evolución de EP. • Rasagilina en enfermedad de Parkinson inicial. • Rasagilina en enfermedad de Parkinson moderado-avanzado. • Perfil de seguridad y alertas con Rasagilina.
- 63. Selectividad de Monoamino-oxidasa (MAO) • Enzima responsable de la degradación de catecolaminas (dopamina, nor- adrenalina) y serotonina. • Dos isoformas: – MAO-A: Primordialmente en hígado y tracto gastro-intestinal. – MAO-B: Primordialmente a nivel cerebral. • La selectividad de la inhibición de la MAO-B es dosis-relacionada: – A bajas dosis, sólo se inhibe MAO-B. – A altas dosis, también se inhibe MAO-A. • Funciones de deaminación: – Tipo A: Predomina en intestino, a nivel de serotonina (5-HT) y noradrenalina (NE). – Tipo B: Predomina en SNC, a nivel de dopamina.
- 64. Posibles mecanismos de toxicidad por serotonina Hendidura Sináptica Receptor TriptofanoTerminal Sináptica 5-HTP 5-HT 5-HT TrH AADC 5-HT 5-HT 5-HIAA 5-HT Antidepresivos5-HT 5-HT 5-HT X X IMAO ► 5-HT= Serotonina ► TrH= Triptofano hidroxilasa ► 5-HTP= 5-hidroxi- triptofano ► AADC= Acido Aromatico decarboxilasa ► MAO-A= Monoamine oxidasa tipo A ► 5-HIAA= Acido 5- Hidroxi-indolacético
- 65. Síntomas por toxicidad de Serotonina ► Síntomas Cognitivos ► Confusión ► Agitación ► Ansiedad ► Síntomas Autonómicos ► Hipertermia ► Diaforesis ► Taquicardia ► Hipertensión ► Síntomas Somáticos ► Mioclonías ► Hiperreflexia ► Rigidez muscular ► Tremor
- 66. Seguridad de Rasagilina con ISRS • Resultados del studio PRESTO en 472 EP avanzado. • 77 pacientes tratados con ISRSs • Excepto vómitos (5% vs 1%), no diferencias significativas en EAs entre pacientes ISRSs positivos e ISRSs negativos – Sin embargo, pacientes con ISRSs, gran compromise basal. • Entre pacientes que recibieron un ISRS, no diferencias en EA entre grupo rasagilina y placebo. • Conclusiones: – “El studio no mostró interacciones deletéreas entre ISRSs y rasagilina en pacientes con EP avanzado” – “Rasagilina fue segura y efectiva.”
- 67. Buena tolerabilidad en la administración concomitante de Rasagilina y escitalopram
- 68. Potenciales interacciones de Selegilina y Rasagilina Csoti I, et al. Basal Ganglia 2012; 2:S27-S31.
- 69. Probable interacción de tiramina con MAO Tiramina Acido Hidroxifenilacético (inactivo) MAO-A Respuesta Simpatomimética Presión Arterial Desplazamiento de Norepinefrina (NE) Tiramina Inhibidor No Selectivo MAO MAO-A NE NE NENE NENE NE NE NE X
- 70. 5 estudios no han demostrado interacción de tiramina con rasagilina a dosis aprobadas para EP 1. Reto de tiramina en 27 sujetos sanos1 – Rasagilina 1mg, 2mg con 800 mg HCL de tiramina. 2. Reto de tiramina en 20 pacientes con EP2 – Rasagilina 1mg, 2mg con 75 mg HCL de tiramina. 3. PRESTO, monitoreo de PA domiciliario en 443 pacientes con EP3 – Rasagilina 0.5mg, 1.0mg + CD/LD con dieta habitual. 4. PRESTO, retos de tiramina en 55 pacientes con EP4 – Rasagilina 0.5mg, 1mg + CD/LD con 50 mg HCL de tiramina. 5. TEMPO, retos de tiramina en 55 pacientes con EP4 – Rasagilina 1mg, 2mg with 75mg HCL de tiramina.
- 71. Conclusiones: Rasagilina en Enfermedad de Parkinson • EP es una enfermedad neurodegenerativa, altamente incidente, con síntomas heterogéneos, más allá de los síntomas motores. • La degeneración neuronal no sólo compromete el sistema dopaminérgico. • El tratamiento debe ofrecer la mejoría de síntomas motores y no motores. • Rasagilina podría tener un rol neuroprotector. • Rasagilina ha demostrado ser eficaz como monoterapia en estadios iniciales de la EP. • Rasagilina produce mejoría adicional cuando es asociado a otros medicamentos dopaminérgicos en estadios avanzados de la enfermedad. • Escasa posibilidad de interacciones.
- 72. Los esperamos…….
Notas del editor
- At 2009, an estimated 5 million people throughout the world have PD, with 1 million individuals each in the United States and in Europe with the disorder. PD affects approximately 0.3% of the population and 1% to 2% of those older than 60 years. With the aging of the population and the substantial increase in the number of at-risk individuals older than 60 years, it is anticipated that the prevalence of PD will increase dramatically in the coming decades.
- In substantia nigra it is cytoplasmic, round, eosinophilic with clear halo. In cortex less distinct appearance, best visualized with alpha-synuclein immunohistochemistry
- A staging system, based on the number and location of LBs, with a caudal to rostral six-stage progression has been proposed for sporadic PD (Braak et al.,2003). The first two stages, with LB pathology involving medulla oblongata and pontine tegmentum, are considered asymptomatic or pre symptomatic and may explain the early non-motorsymptoms (autonomic ando lfactory). Stages 3 and 4, with extension of LB pathology to mid brain and basal prosencephalon and mesocortex, have been correlated to clinical symptomatic stages. The terminal stages 5 and 6, characterized by widespread neocortical LB degeneration, are correlated with significant cognitive decline associated with severe parkinsonism (Hurtigetal.,2000). Although there is an acceptable correlation between pathological findings and clinical data in this staging system, mainly in a subgroup with early onset and prolonged duration (Hallidayetal.,2008), recent studies revealed exceptions to the general order of progression suggested by Braak and colleagues (Jellinger,2008; Parkkinen et al.,2008; Dickson etal.,2009; Kalaitzakisetal.,2009). Another interesting observation from a number of recent clinico-pathological studies that assessed the progression of pathology in subtypes of PD is that in patients with non-tremor-dominant and postural instability and gait dominant clinical pictures there are significantly more cortical LBs and amyloid β plaques compared with tremor dominant or younger onset patients (Selikhova et al.,2009;Halliday et al.,2011). Furthermore, PD patients with dementia have higher amounts of cortical αSyn pathology as compared to those without dementia and a correlation between its severity and AD pathology is also present in such patients (Hallidayetal.,2011).
- 98.6% of patients with Parkinson’s disease reported the presence of NMS. The frequency of NMS increased with the duration and severity of the disease.
- Logistic regression analyses revealed a significant correlation of orthostatic hypotension and urinary incontinence with age and the duration of Parkinson’s disease. Sleep disturbances were more common in women and were correlated with disease duration supporting the observation that sleep is affected in Parkinson’s disease.
- (N=242) NMS in Parkinson’s disease are frequently undeclared at routine hospital visits and this may be due to the patients not linking these symptoms to Parkinson’s disease.
- The gold standard for symptomatic therapy of PD is a pharmacological regimen based on dopamine replacement with the pro-drug levodopa (L-DOPA) in combination with an inhibitor of its peripheral conversion to dopamine (carbidopa or benserazide). L-DOPA does not effectively relieve all of the features associated with PD. In particular, postural instability, tremor, and the majority of non-motor manifestations are less likely to respond to current therapy. Furthermore, long-term treatment with L-DOPA commonly leads to progressive loss of efficacy, the development of dyskinesias in a high percentage of patients within 5 years of therapy, and multiple non-motor manifestations [7–9]. Given the adverse effects and limitations of current therapeutic regimens, there is an urgent need for improved pharmacological options. Although there have been very limited clinical advancements for the pharmacological treatment of PD since the approval of L-DOPA more than 40 years ago, results from recent clinical and preclinical trials will provide a basis for new therapeutic avenues. This review highlights novel strategies that specifically target receptors or transporters of the major neurotransmitter systems of the brain to correct signaling abnormalities associated with PD or L-DOPA-induced dyskinesia (LID). We discuss the rationale of these efforts and identify areas requiring further investigation to develop suitable pharmacological treatment strategies and novel drug tar-gets for more effective management of PD. Basis for limited success of clinical trials for PD PD is associated with a unique combination of the brain regions involved and complex changes in various modulatory pathways. As outlined below, these changes include specific alterations in the expression levels of neurotransmitter receptors and transporters that change over the course of the disease. Unfortunately, a significant fraction of past and current clinical trials involve test compounds that are not optimized to treat the signaling abnormalities specific to PD. Instead, many drug candidates were initially designed for the treatment of different disorders. Although some of these molecules may still prove useful in complementing existing pharmacological therapies, they do not necessarily represent innovative strategies nor are they maximally efficacious for treating a particular feature of PD.
- Pathologically, PD is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) coupled with intracytoplasmic proteinaceous inclusions known as Lewy bodies. It is also now appreciated that PD is associated with extensive non dopaminergic pathology, which involves cholinergic neurons of the nucleus basalis of Meynert, norepinephrine neurons of the locus coeruleus, serotonin neurons in the midline raphe, as well as neurons in the cerebral cortex, brainstem, spinal cord, and peripheral autonomic nervous system. Indeed, recent studies suggest that non dopaminergic pathology, particularly in the dorsal motor nucleus and olfactory regions, precedes the onset of dopaminergic pathology in the SNc.
- Excitatory fibers are shown in black and inhibitory fibers in white. The model predicts that neuronal firing in the STN and GPi are increased in the parkinsonian state, leading to excessive inhibition of brainstem and thalamocortical neurons with the development of parkinsonian motor features. In contrast, the model proposes that dyskinesia is related to decreased firing in the STN and GPi, with reduced inhibition of thalamic and cortical motor regions. SNc substantia nigra pars compacta; GPe external globus pallidus; STN subthalamic nucleus; VL ventralis lateralis; Gpi internal globus pallidus; SNr substantia nigra pars reticularis; PPN pedunculopontine nucleus; DA dopamine. Reproduced from Obeso et al.265
- Note that the basal ganglia network is stabilized by multiple feedback and feed forward loops, and by the modulatory effects of dopamine, which extends throughout the basal ganglia system, thalamus, and cerebral cortex, and is not confined to the striatum. SMA supplementary motor area; GPe external globus palidus; STN subthalamic nucleus; CM-PF centre me´dian-parafascicular; SNc substantia nigra pars compacta; Gpi internal globus pallidus. Modified from Obeso et al.270 with permission from Elsevier. It is now appreciated that the basal ganglia are more complex than had been appreciated and are comprised of a complex network of neurons with many feedback and feed forward loops. Furthermore, it is clear that encoded information is transmitted by way of multiple neurophysiologic parameters, rather than the linear frequency-dependent system depicted by the classic model. Dopamine innervation is now known to extend throughout the entire basal ganglia system, as well as to the thalamus and cortex, and is not restricted to the nigrostriatal system. In addition, it is now appreciated that physiologic information in basal ganglia output neurons is conveyed by more than just firing frequency (e.g., pauses, bursts, synchrony). It is likely that it is the disruption of an abnormal neuronal firing pattern that accounts for the beneficial effects of pallidotomy on dyskinesia. A more modern schema of the basal ganglia illustrating some of these features is provided in this figure. A clear picture of the role of dopamine in the normal basal ganglia and the factors responsible for the origin of motor complications have begun to emerge. Historically, it was noted that the duration of motor benefit after cessation of a levodopa infusion progressively decreased with increasing disease severity, despite all groups having comparable plasma levodopa pharmacokinetics. These findings gave rise to the notion that motor fluctuations in patients with advanced PD are associated with a decreased capacity to store dopamine because of the loss of dopaminergic terminals. However, similar findings were observed with apomorphine, which is not stored in dopaminergic terminals; these findings cannot be explained by the “storage hypothesis.” Furthermore, shortening of the duration of the motor response occurs with repeated doses of levodopa in 6-OHDA-lesioned rodents with stable brain lesions whose capacity to store dopamine has presumably not changed. These findings suggest that there must be a postsynaptic component to the development of motor complications. It is now apparent that motor complications are related, at least in part, to abnormal pulsatile stimulation of dopamine receptors, with consequent dysregulation of genes and proteins in striatal neurons leading to altered neuronal firing patterns in basal ganglia output neurons. Under normal circumstances, striatal dopamine is maintained at a relatively constant level, and there is continuous stimulation of striatal dopamine receptors. SNc dopaminergic neurons normally fire in both a tonic (continuous) and phasic (intermittent bursts) manner. Under normal circumstances, approximately half of the SNc dopamine neurons fire tonically, in a continuous but random manner, independent of movement. Firing of individual SNc dopamine neurons is regulated by GPi–SNc inhibitory neurons. Tonic firing leads to continuous dopamine release, with activation of extrasynaptic D1 receptors by way of volume transmission. Phasic or burst firing of dopamine neurons is glutamate mediated and occurs in response to anticipation of reward or novel stimuli. Burst firing releases large quantities of dopamine, which activate D1 and D2 receptors located within the synapse. Neurons that undergo burst firing, however, contain large numbers of DATs and have a robust dopamine reuptake capacity. Thus, striatal dopamine levels remain relatively constant in the physiologic state, independent of the SNc neuronal firing rate. The constant firing of SNc dopamine neurons, stable striatal dopamine levels, and continuous activation of striatal dopamine receptors are essential for normal basal ganglia function. Under physiologic conditions, dopamine acts presynaptically to modulate the glutamate-mediated excitability of striatal neurons (in both up and down directions) and to influence plasticity (long-term potentiation and long-term depression). Dopamine also acts postsynaptically to inhibit excitation in the indirect pathway and to activate the inhibitory effects of the direct pathway. In these and other ways, dopamine acts to stabilize the basal ganglia network. This is not the case in PD, where there is prominent dopamine depletion and striatal dopamine levels are dependent on the peripheral availability of levodopa. In this situation, replacement of striatal dopamine with intermittent (and discontinuous) doses of standard formulations of levodopa does not restore basal ganglia function to normal. Here, fluctuations in levodopa plasma concentration caused by the short half-life of the drug are directly translated to the striatum, and individual doses of levodopa induce large oscillations in striatal dopamine levels. Indeed, PET studies in fluctuating patients with PD show evidence of oscillating synaptic dopamine levels after individual doses of levodopa. Under these circumstances, striatal dopamine receptors are exposed to intermittently high and low concentrations of dopamine after each dose of levodopa. This nonphysiologic, discontinuous, or pulsatile stimulation of dopamine receptors leads to a variety of molecular and physiologic changes that are associated with the development of motor complications. These include alterations in levels of expression in striatal neurons of a variety of genes including preprodynorphin, delta fos-b, delta c-fos, and preproenkephalin, which have been observed in striatal neurons of dyskinetic rodents, primates, and patients with PD; and changes in neuronal firing pattern (e.g., frequency, bursts, pauses, synchronization) in basal ganglia output neurons. More recently, it has been shown that levodopa treatment and the development of dyskinesia are associated with alterations in plasticity, and with translocation of NR2B subunits of the NMDA receptor from a synaptic to an extrasynaptic location. Interestingly, manipulations of the NR2B subunit can either induce or eliminate dyskinesia in rodents. Furthermore, levodopa impairs depotentiation of striatal neurons, which might contribute to the persistence of undesired behaviors such as dyskinesia. These studies illustrate that the intermittent manner in which we administer levodopa therapy does not normalize the parkinsonian brain, but rather destabilizes the already unstable basal ganglia. Two factors are known to promote pulsatile stimulation of the dopamine receptor: a) the degree of loss of striatal dopaminergic terminals, with a consequent loss in their capacity to buffer fluctuations in striatal dopamine; and b) intermittent doses of a dopaminergic agent with a short half-life, such as levodopa. There is considerable experimental evidence supporting the notion that pulsatile stimulation of striatal dopamine receptors contributes to the induction of levodopa-induced motor complications. Levodopa induces shortening of the motor response (wearing-off) in parkinsonian rodents when it is given intermittently but not when it is administered continuously. Short-acting dopaminergic agents such as levodopa are more prone to induce dyskinesia in MPTP-treated monkeys than are long-acting dopaminergic agents such as bromocriptine and ropinirole. Of particular importance is the observation that the same short-acting dopaminergic agent that induces dyskinesia when administered in a pulsatile manner does not induce dyskinesia when administered continuously. For example, intermittent doses of the short-acting dopamine agonist apomorphine induce severe dyskinesia in MPTP primates, whereas continuous infusion of the same agent does not. These different patterns (pulsatile and continuous) of dopamine receptor stimulation are likely to elicit different functional responses, because they activate different signal transduction pathways in postsynaptic neurons. These examples serve to illustrate that the same dose of the same molecule can induce, or not induce, dyskinesia, depending on the mode of administration. In the final analysis, motor complications likely relate to miscoded information being relayed from basal ganglia output neurons to brainstem and cortical motor regions. It is the elimination of this abnormal neuronal firing pattern that presumably accounts for the antidyskinetic effect of pallidotomy and DBS. On the basis of these considerations, it has been hypothesized that therapies that deliver levodopa or other dopaminergic agents in a more continuous manner will provide antiparkinsonian effects with a reduced risk of causing motor complications. This concept has become known as CDS. Indeed, multiple clinical trials have demonstrated that long-acting dopamine agonists induce less dyskinesia and wearing-off in patients with PD than does levodopa, and continuous infusion of levodopa or a dopamine agonist can reduce established motor complications in patients with advanced PD.
- Dopaminergic (DA) projection pattern and distribution of dopamine receptors in the brain. DA neurons in the substantia nigra (SN) and ventral tegmental area (VTA) represent the two largest DA cell clusters in the mammalian brain. Axons of DA neurons in the SN project mainly to the dorsal striatum (nigrostriatal system), with a small percentage innervating specific areas of the cortex and nucleus accumbens. Some collaterals from projections to the dorsal striatum also innervate extrastriatal nuclei, including the globus pallidus (GP). Whereas only a small number of VTA neurons project to the dorsal striatum, DA VTA neurons primarily innervate the nucleus accumbens and several cortical areas (mesolimbic and mesocortical DA systems). DA VTA neurons also project to additional structures including the hippocampus and hypothalamus. Dopamine receptors are widely expressed in the human brain [20,21]. D1 mRNA expression levels are highest in the dorsal striatum and nucleus accumbens, but are also found in the cortex and at lower levels in the hippocampus, thalamus, and hypothalamus. Similar to D1, the D2 receptor is highly expressed in spiny projection neurons (SPNs) in the dorsal and ventral striatum. D2 mRNA is also expressed in cortex, hippocampus and hypothalamus. Moreover, DA neurons of the SN and VTA express D2 autoreceptors. D3 is present in particular in the nucleus accumbens, with only very low levels in the dorsal striatum, hippocampus, and cortex. Low levels of D3 autoreceptors have been detected in SN and VTA neurons. However, D2 is much more abundant in these neurons than D3 is. Of note, D3 receptors have also been detected in the terminals of striatal neurons that project to the GP. D4 shows the lowest expression levels among all DA receptors in the basal ganglia. Brain regions with detectable levels of D4 mRNA include the cortex, hippocampus, and hypothalamus. Moreover, GABAergic neurons in the GP express D4. Similar to the D4 receptor, D5 is expressed at much lower levels than D1 and D2. The D5 receptor has been detected in the cortex, dorsal and ventral striatum, hypothalamus, and hippocampus. In the dorsal striatum, D5 is localized in SPNs and in cholinergic interneurons. Low levels of D5 have also been detected in the SN. Abbreviations: Nucl. acc., nucleus accumbens. Autoreceptors are underlined.
- Raphe nuclei (RN) and distribution of serotonin receptors in the brain. Dorsal RN innervate several regions of the basal ganglia, including the striatum, ventral tegmental area (VTA), substantia nigra (SN) pars reticulata, and to a lesser extent SN pars compacta. Moreover, serotonergic (5-HT) neurons in the brainstem project to limbic brain areas, including the cortex and hippocampus. 5-HT neurons innervate both dopaminergic (DA) neuronal cell bodies of the SN and the region of their terminal projections in the striatum. The anatomical interaction of the 5-HT system with DA components of the basal ganglia facilitates functional modulation of DA neurotransmission by serotonin in the normal, non-parkinsonian brain [40]. 5-HT receptors are classified into seven families that comprise at least 14 different receptor subtypes. For most 5-HT receptors, expression has been described in the human brain [41,42]. Receptor autoradiography studies revealed a high density of postsynaptic 5-HT1A binding sites in limbic areas, including the hippocampus and cortex. Presynaptic 5-HT1A receptors were detected on RN cell bodies and dendrites. 5-HT1B mRNA levels are high in the human dorsal striatum, nucleus accumbens, cortex, and RN. Lower levels were measured in the hippocampus. In situ hybridization analyses in rat brain mapped low 5-HT1D mRNA expression levels to the dorsal striatum, nucleus accumbens, and RN. 5-HT1B and 5-HT1D receptors are mostly located in the nerve terminals of neurons that project to other brain regions. Although the SN and globus pallidus (GP) display binding sites for 5-HT1B and 1D, mRNA was not detected in these two regions. Both receptors also serve as autoreceptors on RN neurons. 5-HT1E binding sites and mRNA were mapped to the human cortex and dorsal striatum. The expression of 5-HT1F receptor is very low. 5-HT2A mRNA and protein are highly abundant in the cortex, dorsal striatum, nucleus accumbens, and hippocampus. 5-HT2B mRNA and protein levels are very low in hippocampus and cortex. No signal was detected in basal ganglia. 5-HT2C binding sites and mRNA were detected in the dorsal striatum, nucleus accumbens, cortex, and hippocampus. 5-HT2C mRNA expression in DA neurons of the SN and VTA was demonstrated in some studies. However, those findings are controversial. In humans, 5-HT3 receptor binding sites are highly abundant in spiny projection neurons (SPNs) of the dorsal striatum and in the hippocampus, with a lower signal detected in the cortex. 5-HT4 mRNA and binding sites were detected in striatal SPNs. 5-HT4 binding sites in the GP and SN are derived from striatal projections. 5-HT5 mRNA was mainly detected in the cortex. 5-HT6 mRNA and protein are present in SPNs in the dorsal striatum and nucleus accumbens, as well as in the hippocampus. In rodents, 5-HT7 mRNA and binding sites are highly abundant in the hippocampus, with lower levels measured in the cortex. Abbreviations: Nucl. acc., nucleus accumbens. Autoreceptors are underlined.
- Noradrenergic (NA) projections and expression pattern of norepinephrine (NE) receptors in the brain. The locus coeruleus (LC) in the pons is the main NA nucleus in the mammalian brain. NA neurons project to multiple regions of the basal ganglia and the limbic system including dopaminergic (DA) neurons of the substantia nigra (SN) and the ventral tegmental area (VTA), the striatum, neocortex, hippocampus, hypothalamus, and cerebellum. Besides NE, the LC produces various additional neuromodulators, including enkephalin, brain-derived neurotrophic factor, neuropeptide, and galanin. Similar to DA neurons in the SN, cells of the LC are pigmented due to the presence of neuromelanin. Adrenoceptors are subdivided into three major groups. The different receptors are characterized by distinct expression patterns in the brain as demonstrated by various autoradiographic studies. In human postmortem tissue, abundant levels of a1, a2, b1, and b2 receptors were detected in the cortex, hippocampus, hypothalamus, and cerebellum [48–51]. In the striatum, b1 and b2 receptors are most abundant, whereas only very low signals were measured for a1 and a2. Expression studies of adrenoceptors in human SN suggest the presence of a1 and b1 receptors in this brain region. By contrast, very low signals were obtained for a2 and b2. a2 receptors are also located on NA LC neurons, where they function as autoreceptors. Moreover, very low levels of b3 mRNA were detected in adult cortex, striatum, and SN [52]. Autoreceptors are underlined.
- Levodopa is the most effective drug for the symptomatic treatment of PD and the gold standard against which new therapies must be measured. Indeed, no other medical or surgical therapy currently available has been shown to provide antiparkinsonian benefits superior to what can be achieved with levodopa. Virtually all patients with PD experience clinically meaningful benefits with levodopa treatment, with improvements in activities of daily living, quality of life, independence, and employability. Benefits are usually seen in all stages of the disease and can be particularly noteworthy in patients with early PD, in whom the drug can control virtually all of the classic motor features. Importantly, levodopa treatment is associated with decreased morbidity and mortality compared with treatment in the pre levodopa era, although patients with PD continue to have mortality rates higher than age-matched controls. Levodopa is routinely administered in combination with a decarboxylase inhibitor, to prevent its peripheral conversion to dopamine and the development of side effects such as nausea, vomiting, and orthostatic hypotension due to stimulation of dopamine receptors in the area postrema that are not protected by the blood-brain barrier. In the United States, levodopa is combined with the decarboxylase inhibitor carbidopa and marketed as Sinemet. Dosage strengths of 10/100, 25/100, and 25/250 mg are available, with the first number representing the dose of carbidopa and the second number representing the dose of levodopa. In Europe, levodopa is combined with the decarboxylase inhibitor benserazide and sold under the trade name of Madopar; it is available in doses of 25/100 and 50/200 mg, as well as in a 25/100 mg water-dispersible tablet. Parcopa is an orally dissolving form of levodopa/carbidopa that requires no liquid intake and may be useful for patients with swallowing difficulties. A combination of carbidopa/levodopa and the COMT inhibitor entacapone (Stalevo) is available and marketed in formulations containing 50, 75, 100, 150, and 200 mg of levodopa. A liquid preparation of levodopa can be made from regular formulations of the agent by adding the drug to water in the presence of ascorbic acid; the preparation has to be freshly made and cannot be stored, however, and it has not been established to provide more rapid absorption than can be achieved with multiple oral doses of standard formulations of levodopa. Sustained-release formulations of Sinemet (Sinemet CR) in doses of 25/100 and 50/ 200 mg, and Madopar (Madopar HBS) in doses of 50/200 mg, are available. A formulation that combines immediate- and controlled-release forms of levodopa in a single tablet (Vadova) has recently been approved in some countries. Methyl ester formulations of levodopa are also available in some countries and offer a possible advantage over traditional levodopa, in that they are more rapidly and predictably absorbed. This prodrug of levodopa has greater gastric solubility, rapid transit into the small intestine, and is rapidly hydrolyzed to form levodopa before absorption. The pharmacokinetic profile of these prodrugs suggests that they might provide more rapid and more predictable “on” episodes in fluctuating patients with PD who experience “delayed-on” or “no-on” responses. A gel preparation of levodopa (Duodopa) has been used for intraintestinal infusion of the agent and is available in many countries in Europe. Parenteral forms of levodopa may be particularly valuable in the management of patients with PD who undergo surgery and cannot take medications orally. Levodopa is absorbed in the small bowel by active transport through the large neutral amino acid (LNAA) pathway, and can be impaired by alterations in gastrointestinal motility and by dietary LNAAs, such as phenylalanine, leucine, and valine, which compete with levodopa for absorption through the LNAA. Similar absorption problems can occur with Parcopa, which is absorbed through the intestine even though it dissolves in the mouth. Acute side effects associated with levodopa include nausea, vomiting, and hypotension. Levodopa is generally started at a low dose to minimize these risks. Patients are then gradually titrated to an effective dose over weeks or months. Traditionally, levodopa has been initiated two or three times daily using the lowest effective dose, although there have been no studies designed to determine the optimal way to administer the drug. In the early stages of the disease, motor control can usually be accomplished with a total daily dose of 300 to 400 mg/day. In some patients, larger dosages may be required to achieve a therapeutic benefit and levodopa doses of 1,000 mg/d or higher must be administered for several weeks or months before a patient can be said to be nonresponsive. Patients with PD who fail to respond to high doses of levodopa (1,200 mg) probably have an atypical parkinsonism rather than PD and are unlikely to respond to other dopaminergic drugs. Sustained-release formulations of levodopa are not as well absorbed as regular formulations, and doses 20% to 30% higher may be necessary to achieve the same clinical effect. It is usually best to administer levodopa when the patient has an empty stomach, to facilitate absorption and avoid competition with dietary proteins, even though many pharmacists label for levodopa to be taken with meals. A practical approach is to dose levodopa 1 hour before or 1 hour after eating. Decarboxylase inhibitors such as carbidopa are typically administered in a dose of 75 mg/d, to inhibit decarboxylase activity and prevent dopamine related side effects. If a patient is on a small dose of Sinemet or Madopar, it may not contain enough of the decarboxylase inhibitor to adequately inhibit the decarboxylase enzyme, and in some individuals it may be necessary to provide additional doses of carbidopa (Lodosyn), which is available in 25 mg tablets. Occasionally, patients require as much as 300 mg of supplemental carbidopa to prevent levodopa induced nausea or vomiting. Supplemental carbidopa can usually be discontinued when higher doses of Sinemet are used or after the patient has developed tolerance to the nausea and vomiting. The peripheral dopamine-receptor antagonist domperidone, in doses of 10 to 20 mg administered 30 minutes before each levodopa dose, can be effective in preventing nausea and vomiting, but this drug is not yet available in the United States. Trimethobenzamide hydrochloride (Tigan) 200 mg TID can be used in its stead but is not generally as effective. With the use of these strategies (extra carbidopa or addition of an antiemetic), it is rare for a patient with PD to be unable to tolerate levodopa because of acute side effects. If, however, orthostatic hypotension is prominent and does not attenuate over time, or respond to carbidopa or domperidone, the possibility that the patient might have MSA rather than PD should be considered. Chronic levodopa therapy is associated with motor complications, such as dyskinesias and motor fluctuations, in the majority of patients. These can represent a source of disability for some patients and limit the ability to fully use levodopa to control parkinsonian features. Patients with PD can also experience fluctuations in such non motor symptoms as mood, cognition, autonomic disturbances, pain, and sensory function. Levodopa may also be associated with neuropsychiatric side effects, including cognitive impairment, confusion, and psychosis. Importantly, many PD features are not satisfactorily controlled by, or do not respond to, levodopa. These include freezing episodes, postural instability with falling, autonomic dysfunction, mood disorders, pain and sensory disturbances, and dementia. Levodopa treatment can also be associated with a dopamine dysregulation syndrome in which patients compulsively take extra doses of levodopa in an addictive fashion. They may also experience punding, which consists of repetitive, complex, nonproductive behaviors such as purposeless arranging and rearranging of objects. Although levodopa has been associated with impulse control disorders (ICDs) such as hypersexuality and pathologic gambling, these behaviors have primarily been reported to be associated with dopamine agonists.
- Although levodopa effectively treats the motor symptoms of Parkinson’s disease (PD), its long-term administration usually results in the emergence of levodopa-related motor complications. In the CALM-PD trial (Comparison of the Agonist Pramipexole versus Levodopa on Motor Complications of Parkinson’s Disease), 301 subjects with early PD were randomised to initial treatment with pramipexole or levodopa over a period of 4 years. Open-label levodopa could be added in either treatment group after 10 weeks, if needed, to treat emerging motor symptoms. This slide compares the occurrence of motor complications in early PD patients that maintained pramipexole monotherapy (n = 44) with those patients receiving supplemental levodopa in either the pramipexole- or levodopa-treatment groups over the 4-year duration. Dyskinesia was not reported as an adverse event in patients who were maintained on pramipexole monotherapy. The addition of supplemental levodopa resulted in an increased rate of motor complications as measured by reports of dyskinesia as an adverse event and as a response to the single question asked at each visit “Have you experienced any involuntary movements?” Nevertheless, the rate of motor complications in these patients remained substantially lower than the reported rate in the levodopa group. Long-term follow up for six years confirmed the delay in the development of motor complications (dyskinesias and wearing off) for patients initiated on pramipexole, although this group had more somnolence as an adverse event. Consequently, in early PD patients, if pramipexole monotherapy can be maintained without the addition of levodopa therapy or if the addition of supplemental levodopa can be delayed, the risk for developing dyskinesia as the disease progresses may be greatly reduced.
- Dopaminergic Treatment: Highly effective for the classic motor features Tremor, rigidity, bradykinesia Do not satisfactorily control non-dopaminergic features Gait dysfunction, freezing, postural instability, falling, autonomic dysfunction, mood disorders, sensory problems, cognitive impairment, dementia. Do not stop disease progression
- Se ha hipotetizado que levodopa puede ser toxica a las celulas de la sustancia negra y por ende puede promover la progresion de la enfermedad, no obstante, a la fecha no existe soporte convincente de datos en animales o en humanos. El estudio ELLDOPA comparo clinicamente y atraves de imagenes pacientes que recibieron diferentes dosis de levodopa comparado con placebo en el curso de 40 semanas con un periodo de 2 semanas de wash-out. Los pacientes que tomaron levodopa experimentaron menos deterioro de la funcionalidad entre el basal y las 40 semanas de tratamiento, comparado con los que tomaron placebo (Los pacientes que recibieron placebo empeoraron el UPDRS en 8 puntos, los pacientes que recibieron 150 y 300 mg/d de levodopa empeoraron en 2 puntos, mientras que los pacientes que recibieron 600 mg/d de levodopa mejoraron en 1.5 puntos), pero no queda claro si estos hallazgos representan un efecto sintomatico persistente. Los hallazgos se complican a la luz de los resultados de las imagenes, pues los datos muestran que los pacientes que recibieron levodopa tienen una gran perdida de la recaptacion de dopamina, en relacion a los pacientes que tomaron placebo. At the completion of the trial, patients who had been randomly assigned to receive L-dopa had less deterioration from baseline than did those on placebo showing no evidence of toxicity and even consistent with neuroprotection. However, as part of this study a subgroup of patients underwent b-CIT SPECT scans at baseline and at 9 months. Patients treated with L-dopa had a greater rate of decline in this imaging marker than did those in the placebo group, consistent with L-dopa having a toxic effect. Here too, the results of the study are difficult to interpret. The clinical improvement in the L-dopa arms after 2 weeks of washout could relate to a long duration benefit of L-dopa that persists after the washout period. Alternatively, the sustained clinical benefit following washout could be interpreted as a neuroprotective effect of L-dopa. At the clinical level, these results do not suggest that L-dopa is toxic. In contrast, the imaging results could suggest a toxic effect of L-dopa on nigrostriatal cells, or alternatively a down regulation of the transporter such as was suggested for the dopamine agonist neuroprotection trials. A further possibility is that earlier treatment in itself had a protective effect which would be consistent with the results from a number of other studies.
- The ELLDOPA study did clearly establish the dose response effectiveness of L-dopa in these early PD patients, but also showed that motor complications were dose-related and could develop within 6 months of initiation of L-dopa, reaching levels of 30% for wearing off and 16.5% for dyskinesias in the high dose group.
- En el análisis de la captacion de dopamina a nivel del putamen, usando fluorodopa por PET se encontró una diferencia relativa de 35% (p=0.022) entre ambos tratamientos a los 2 años. NOTA: Un cambio negativo del porcentaje revela una perdida de la neuronas dopaminergicas estriatales o progresion de la enfermedad. Por ejemplo, si el paciente empieza con captacion de dopamina de 20, y luego de 2 años, ahora capta como 12, la diferencia a los 2 años es: 12-20 = -8.
- De manera similar, los pacientes que reciben pramipexole tras 4 años comparado alcanzan una diferencia de 40% en la captación de dopamina (aunque aqui se realizó SPECT con β-CIT) respecto de levodopa. Ahora, queda la duda, sí realmente estamos asistiendo a la evidencia de neuroproteccion por los agonistas o si es a evidencia de neurotoxicidad por levodopa, pués en ninguno de los casos tenemos grupo control con placebo.
- The principal statistical analysis incorporated three primary efficacy hypotheses tests which analyzed in a hierarchical manner the change from baseline in total UPDRS score (sum of parts I, II, and III). The first primary efficacy hypothesis compared the rate (slope estimate) of UPDRS progression during the placebo controlled phase from week 12 to week 36 between the placebo- and rasagiline-treated arms (1 and 2 mg groups). All available post baseline observations in the PC phase of the trial were analyzed (weeks 12, 24 and 36). The placebo groups were combined to one placebo group. Statistical model: Repeated Measures Mixed Linear Model with random intercept and slope The second primary efficacy hypothesis compared the estimate of change from baseline to week 72 in total UPDRS score between the early start and delayed start groups for each dose (1 and 2 mg). The least square means (LSM) at week 72 of the change from baseline in Total UPDRS was compared between the 1mg early-start group and the 1mg delayed-start group and between the 2mg early-start group and the 2mg delayed-start group. The third hypothesis tested for non inferiority of the slope estimates of the early-start and delayed-start rasagiline groups (1 and 2 mg) during the active phase of the trial (weeks 48 to 72). This analysis determines if any separation between the groups at the end of phase I persists, or if the slopes of the curves tend to converge. A non-inferiority margin of 0.15 UPDR S units per week was selected according to power calculation considerations Statistical model: Repeated Measures Mixed Linear Model with random intercept and slope Mixed models repeated measures analysis of covariance was used for all hypothesis statistical tests and parameter estimates. The model included the following fixed effects: treatment group, week in trial, week by treatment interaction, center, and baseline total UPDRS score. To maintain an experiment-wide type I error of .05, the Hochberg-Step up Bonferoni method was used to account for multiple comparisons between treatment groups and the hierarchal method will be used to account for multiple primary analyses. Hierarchal endpoints involve testing multiple hypotheses in a sequential manner.
- ADAGIO comprised of 2 phases: phase I: 36-week double-blind, placebo-controlled; and phase II: 36-week double-blind, active-treatment phase in which all patients are on active study intervention. After obtaining IRB-approved informed consent, subjects were randomized in a 1:1:1:1 ratio into one of the following four treatment groups, based on a randomization scheme with blocks stratified by center 1 mg/day rasagiline during phase I and phase II (1 mg early start) 2 mg/day rasagiline during phase I and phase II (2 mg early start) Placebo during phase I followed by 1 mg/day rasagiline during phase II (1 mg delayed start) Placebo during phase I followed by 2 mg/day rasagiline during phase II (2 mg delayed start) Thus, ‘early-start’ patients received 72 weeks of treatment with rasagiline (1 or 2 mg once daily) and ‘delayed-start’ patients receive 36 weeks of placebo followed by 36 weeks of rasagiline (1 or 2 mg once daily). If subjects in either treatment group required additional anti-parkinsonian medication during the placebo-controlled phase of the trial, they could proceed directly to Phase II. Once in Phase II, no additional anti-PD therapy was permitted. If the patient required additional medication in this stage they were discontinued from the study. At each visit except at week 4, a UPDRS evaluation was performed. Other evaluations performed at each visit included measures of quality of life, adverse events reporting, and standard laboratory assessments.
- A total of 1,176 patients (61.1% male) from 129 study sites in 14 countries (Argentina, Austria, Canada, France, Germany, Hungary, Israel, Italy, The Netherlands, Portugal, Romania, Spain, the UK and the USA) were enrolled into the study and randomised.1 Overall, the mean age of patients was 62.2 ± 9.6 years, the mean time from diagnosis was 4.5 ± 4.6 months, and mean UPDRS-Total score was 20.4 ± 8.5.1 With a mean disease duration of 4.5 ± 4.6 months and a baseline UPDRS-Total score of 20.4 ± 8.5,1 the population enrolled into the ADAGIO study is one of the earliest PD populations studied to date in a randomised clinical trial.
- Overall illustration of Delayed-Start design with the placebo-controlled phase for the first 6 months followed by the active-treatment phase for the second 6 months. Design of Active Treatment Phase (Second 6 months) In the second 6 month phase of this study with a randomized-start design, subjects originally randomized to 1mg/day or 2mg/day of rasagiline remained on that dosage, while subjects previously on placebo received rasagiline 2 mg/day (designated the “delayed rasagiline” group). Blinding was maintained in all phases. In all, subjects were randomized to one of three treatment groups: (1) rasagiline 1 mg/day for one year; (2) rasagiline 2 mg/day for one year; or (3) matching placebo for six months followed by rasagiline 2 mg/day for six months. Out of the 404 subjects who initiated the TEMPO study, 380 subjects (94%) entered the active treatment phase. At the time of database lock, 224 patients were still participating in the study and 82 patients had prematurely discontinued the study. The two main reasons for early termination were patient request (11%, n=33) and adverse experiences (6%, n=19). Patient Request 33 10.8% Adverse Experience 19 6.2% Other 12 3.9% Unsatisfactory Response 7 2.3% Experience Unrelated 5 1.6% To Therapy Failed to Return 4 1.3% Protocol Violation 1 0.3% Death 1 0.3% Baseline Demographic and Clinical Characteristics Average age at baseline was 61 years. The large majority of participants were Caucasian, and just over half of the group were men. The average PD duration at the time of study entry was 1.2 years. At that time, patients had a mean total UPDRS score of 26.1, and mean Hoehn and Yahr PD severity was rated as 1.9.
- These are the results for the primary endpoint Note: 4-point deterioration in the placebo group over 6 months. No deterioration in rasagiline groups. Benefit of rasagiline is demonstrated by stabilization of UPDRS scores, while the placebo group got worse. Another analysis -- which defines a “responder” as UPDRS change of < 3 points -- showed more responders in the rasagiline groups than in the placebo group1. The magnitude of the effect of rasagiline on the primary endpoint was similar for the 1-mg and 2-mg doses. Maximum score for the total UPDRS, parts I, II and III is 176.
- 441 pacientes recibieron rasagilina como monoterapia inicial en estudios de fase II y III. At year 2 of follow-up, 46% of the patients, or 121 of 266 patients, remaining in the study were still adequately controlled by rasagiline treatment and did not need additional dopaminergic therapy. A los 5 años, 18% de pacientes permanecieron con rasagilina como monoterpaia (n=127)
- Tempo study: Placebo (n=138), Rasagilina 1 mg/d (n=134) ADL medido en escala de 0 a 52. Puntaje promedio basal para placebo fue 6.2 y para Rasagilina fue de 5.9 Mejoría en más de 1.0 unidad comparado con placebo en UPDRS-ADL en pacientes con EP en estadios iniciales tratados con rasagilina como monoterapia inicial (p=0.0003). El UPDRS-ADL incluye vestimenta, hablar, rodar en la cama, cortar alimentos con cuchillo, desplazamiento, escritura a mano, entre otros.
- Estudio PRESTO: The Parkinson Group Study. A randomized placebo-controlled trial of rasagilina in levodopa-treated patients with PD and motor fluctuations. The PRESTO study. Arch Neurol 2005;62:241-248. This graph represents the change from baseline in total daily “OFF” time by visit. Note that by 6 weeks there was reductions in “OFF” time of over 1 hour in both the 0.5 mg and 1.0 mg rasagiline groups. Note again, that there is an apparent dose response relationship.
- En el estudio LARGO, rasagilina 1 mg redujo significativamente los puntajes del UPDRS-ADL durante el tiempo en “off” comparado con el placebo (-1.72 unidades, p=0.0001) En el estudio PRESTO, rasagilina 1 mg redujo significativamente los puntajes del UPDRS-ADL durante el tiempo en “off” comparado con el placebo (-1.36 unidades, p=0.0034).