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