Cerebrolisina - NEUROVASC.mx
Transcription
Cerebrolisina - NEUROVASC.mx
Cerebrolisina Dr. Luis Enrique Amaya Sánchez Isquemia Cerebral • Depende de 3 factores: – Intensidad de la isquemia – Duración de la isquemia – Presencia de circulación colateral Estrategias manejo Infarto Cerebral • Neuroprotección – Intenta reducir tamaño de la lesión isquémica en la fase aguda • Neurorreparación – Dirigida a restaurar el daño cerebral ya establecido • “En la actualidad no se cuenta con un neuroprotector que haya demostrado su eficacia en estudios clínicos controlados” Cantú C, Chiquete E. Clínicas Mexicanas de Neurologia. (1) 2012 Factores que influyen sobre las terapias restauradoras • • • • • Ventana terapéutica Factores ambientales Experiencia Genética Factores que influyen negativamente JAMA 2006;296 Cerebrolisina • Péptido con acción similar a la de los factores neurotróficos • Propiedades neuroprotectoras: – Incrementa número de sinapsis – Estímula células progenitoras neuronales – Promueve migración células progenitoras hacia la zona isquémica – En modelos animales reduce hasta el 65% del infarto cerebral • Los factores neurotróficos son las moléculas endógenas más importantes involucradas en la protección y en la recuperación cerebral Neurotrophic pathway of Cerebrolysin – a multimodal action NTFs Receptors Cerebrolysin Mimetic - direct pathway Shh/ kinases Genes expression Stimulation of NTFs production - indirect pathway Therapeutic effects: Neuroprotection Neurorestoration Support of self-recovery mechanisms Sonic Hedgehog Signaling Pathway Mediates Cerebrolysin-Improved Neurological Function After Stroke Li Zhang, MD; Michael Chopp, PhD; Dieter H. Meier, MD; Stefan Winter, PhD; Lei Wang, MD; Alexandra Szalad, MS; Mei Lu, PhD; Min Wei, BS; Yisheng Cui, MD; Zheng Gang Zhang, MD, PhD Background and Purpose—Cerebrolysin, a mixture of neurotrophic peptides, enhances neurogenesis and improves neurological outcome in experimental neurodegenerative diseases and stroke. The Sonic hedgehog (Shh) signaling pathway stimulates neurogenesis after stroke. The present study tests whether the Shh pathway mediates cerebrolysininduced neurogenesis and improves neurological outcome after stroke. Methods—Rats subjected to embolic stroke were treated with cerebrolysin with or without cyclopamine. Results—Using neural progenitor cells derived from the subventricular zone of the lateral ventricle of adult rats, we found that cerebrolysin significantly increased neural progenitor cells proliferation and their differentiation into neurons and myelinating oligodendrocytes, which were associated with upregulation of Shh and its receptors patched and smoothened. Blockage of the Shh signaling pathway with a pharmacological smoothened inhibitor, cyclopamine, abolished cerebrolysin-induced in vitro neurogenesis and oligodendrogenesis. In the ischemic rats, treatment with cerebrolysin starting 24 hours after stroke significantly increased neural progenitor cell proliferation in the subventricular zone and enhanced neurogenesis, oligodendrogenesis, and axonal remodeling in the peri-infarct area. Moreover, profound neurological function improvements were observed in rats treated with cerebrolysin from week 3 to week 5 after stroke onset compared with vehicle-treated rats. However, in vivo inhibition of the Shh pathway with cyclopamine completely reversed the effects of cerebrolysin on neurorestoration and functional recovery. Conclusions—These results demonstrate that the Shh pathway mediates cerebrolysin-enhanced neurogenesis and white matter remodeling and improves functional recovery in rats after stroke. Stroke. 2013;44:00-00 Cerebrolisina en la terapia del stroke Evidencia clínica •10 estudios randomizados, doble ciego, placebo controlado •Cerebrolisina utilizado de forma concomitante a la terapia básica, estándar del infarto cerebral, comparado con placebo o sólo terapia estándar •N=2228 patientes enrolados •Estudios pequeños en cuanto a número de pacientes Cerebrolysin adjuvant treatment in Broca’s aphasics following first acute ischemic stroke of the left middle cerebral artery Dragos Catalin Jianu, Dafin Fior Muresanu, Ovidiu Bajenaru, Bogdan Ovidiu Popescu, Sanda Maria Deme. Background: The aim of our study was to assess the efficacy of Cerebrolysin administration in Broca’s aphasics with acute ischemic stroke. Methods: We registered 2,212 consecutive Broca’s aphasics following an acute ischemic stroke admitted in four departments of neurology in Romania, between September 2005 and September 2009. Language was evaluated with the Romanian version of the Western Aphasia Battery (WAB). The following inclusion criteria were used for this study: age 2075 years, admission in the hospital within 12 hours from the onset of the symptoms, diagnosis of first acute left middle cerebral artery (MCA) ischemic stroke, presence of large artery disease (LAD) stroke, a NIHSS score of 5-22 points, and a therapeutic time window within 72 h. Fifty two patients were treated with Cerebrolysin (Cerebrolysin group) as an adjunctive treatment. A placebo group, which received saline infusions (n=104 patients) were matched to the NIHSS and WAB scores, gender and age of the Cerebrolysin group at baseline. We assessed spontaneous speech (SS), comprehension (C), repetition (R), naming (N), and Aphasia Quotient (AQ) scores of the two groups in an open label design, over 90 days, the mRS scores and mortality. Results: The Cerebrolysin and the placebo groups had similar age (66+/-8 versus 65+/-8 years) and sex ratio (14/38 versus 30/74). The mean AQ scores and the mean subscores for 3 subtests of WAB (SS, R, N) were similar at baseline and improved in the Cerebrolysin group significantly (p<0.05) over placebo group at all study time points. The mRS score at 90 days was also lower in the Cerebrolysin group than in the placebo group. Cerebrolysin and placebo were both tolerated and safe, and no difference in the mortality rate was seen (3.8% in each group). Conclusion: Cerebrolysin is effective for the treatment of Broca’s aphasics with a first acute ischemic stroke of the left MCA territory. Journal of Medicine and Life Vol. 3, No.3, July‐September 2010, pp.297‐307 Journal of Medicine and Life Vol. 3, No.3, July‐September 2010, pp.297‐307 A prospective, randomized, placebo-controlled, double-blind trial about safety and efficacy of combined treatment with alteplase (rt-PA) and Cerebrolysin in acute ischaemic hemispheric stroke Wilfried Lang, Christian H. Stadler, Zdravka Poljakovic, David Fleet ,and the Lyse Study Group International Journal of Stroke © 2012 World Stroke Organization Vol 8, February 2013, 95–104 Cerebrolisina apoya la reperfusión • Evolution of the National Institutes of Health Stroke Scale (NIHSS) responders for the Cerebrolysin and placebo groups. Defined as improvement of at least 6 points from baseline or total score 0-1. *p<0.05 vs. placebo (30 ml/10 days; immediately after rtPA). Strongest Cerebrolysin treatment effect around day 7 post-stroke Cerebrolisina y movilización temprana Improvement of motor functions after stroke. Mean change from baseline in the Canadian Neurological Scale (CNS) for the Cerebrolysin and placebo groups. Shown is overlap with time window for EM Cerebrolisina en Pacientes de Asia con Accidente Cerebrovascular Isquémico Agudo Resultados de un Estudio Aleatorio, Doble Ciego, Placebo Controlado Wolf-Dieter Heiss, MD*; Michael Brainin, MD; Natan M. Bornstein, MD; Jaakko Tuomilehto, MD, MPolSc, PhD; Zhen Hong, MD*; Investigadores en Asia para el Tratamiento de Accidente Cerebrovascular Agudo con Cerebrolisina (CASTA) Stroke. 2012;43:630-636 Cerebrolisina y movilización temprana • Significant increase in survival rate in Cerebrolysin-treated sub-group with baseline NIHSS>12. Patients were treated for 10 days with a daily dosage of 30 ml. Shown is overlap with time window for EM Cerebrolisina en la terapia del infarto cerebral Los resultados indican efectos benéficos del tratamiento en los pacientes más severamente afectados (NIHSS >12) NIHSS baseline >12 -6 -6 -5 -5 -4 Cerebrolysin -3 Placebo -2 -1 1 2 5 10 0 Day 30 90 Change from Baseline Change from Baseline NIHSS baseline ≤7 -4 Cerebrolysin -3 Placebo -2 -1 1 0 2 5 10 30 90 Day -> ceiling effect in milder cases CASTA trial: n=1070 Hong et al., 2009 Heiss et al., 2012 Cerebrolisina en la terapia del infarto cerebral Los resultados indican reduccion de la mortalidad Cumulated mortality: Placebo 6.6% ∆ = 1.3% Cerebrolysin 5.3% HR 1.26; 97.5% CI-LB 0.75 CASTA trial: n=1070 Hong et al., 2009 Heiss et al., 2012 Cerebrolisina en la terapia del infarto cerebral Los resultados son más destacados en pacientes severamente afectados (NIHSS >12) Cumulated mortality: Placebo 20.2% ∆ = 9.7% Cerebrolysin 10.5% HR 1.97; 97.5% CI-LB 1.00 CASTA trial: nNIH>12=252 Hong et al., 2009 Heiss et al., 2012 Cerebrolisina en la terapia del infarto cerebral El beneficio se observan tempranamente en el curso del tratamiento Percentage of responders: Cerebrolysin treatment phase Responder definitions: mRS: score of 0 or 1 NIHSS: score of 0 or 1 or >6 points improvement BI: score of ≥95 Lysis trial: n=119 Lang et al., 2012 Conclusiones La neuroprotección en el infarto cerebral requiere ser preventiva •Comenzar de forma temprana durante la fase aguda •La estimulación de la recuperación debe ser iniciada tempranamente •Buscar fármacos cuyo efecto sea multimodal •Cerebrolisina es segura y de efecto multimodal •Se requiere diseño de estudios propios y definir la dosis ideal