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NEUROPROTECCIÓN Y
NEURORREPARACIÓN:
EVIDENCIAS CON
COLINERGICOS Y
ANTAGONISTAS NMDA
DR. JUAN MANUEL CALLEJA CASTILLO
NEUROLOGÍA
INNN
CM ABC
NEUROPROTECCIÓN
DÉFICIT
NEURORREPARACIÓN
La Acetil-colina
• Neurotransmisor que en el SNC promueve la
atención y la formación de memorias a corto plazo
• Muy involucrado en atención espacial
(negligencia)
• Lucas 2013
• Los anticolinergicos han demostrado inhibir el
aprendizaje
• Drachman 1974
• Posible efecto sobre el flujo sanguíneo regional a
largo plazo?
• Roman 2006
by promoting the use of drugs combined with SLT in
everyday clinical practice (Endres et al. 2008; Floel and
Cohen 2010). However, much empirical work is needed as
the role of drug treatment of aphasia has been addressed in
fewer than 20 randomized controlled trials and virtually all
of them have served as proof-of-concept investigations
(demonstration of clinical efficacy with a small number of
strictly selected patients) (Liepert 2008; Small and Llano
2009). Although efforts to evaluate the role of relatively
new pharmacological therapies (donepezil, memantine) are
underway (see Pulvermüller and Berthier 2008; Berthier
and Pulvermüller 2011), a further barrier to progress in
refining drug treatment of aphasia is the lack of profit
incentives to test the efficacy of patent-expired medications.
Therefore, the current scenario is that only a small number of
Selden
1998 rehabilitation units receive offaphasic• patients
attending
label treatments with brain-stimulating drugs (dopaminergic
50-year history, yet the results of
approaches were disappointing bec
mented, with few exceptions (Luria
1988), without a theoretical justific
2009). Recent advancesin neuroscien
a renewed impetus to use brain-stimu
the benefits provided by SLT in pa
related cognitive deficits (attention, w
and Albert 2004; McNamara and Alb
de Boissezon et al. 2007; Hillis 2
Berthier 2008; Berthier and Pulverm
One mechanism by which stroke
by interrupting major neurotransmitt
the brainstem and basal forebrain
regions of the cerebral cortex and de
2004; Parton et al. 2005; Cramer
2009). Figure 2 shows the anatomi
Déficit de Acetil-colina en
Infarto cerebral
• Las lesiones isquémicas profundas de sustancia
blanca pueden interrumpir el flujo de vías
colinérgicas y provocar negligencia, inatención,
pobre aprendizaje.
LA EXCITOTOXICIDAD
• Glutamato: Función en aprendizaje y plasticidad
• Exceso de glutamato y activación NMDA: aumento
de flujo de Calcio y muerte celular
• Papel en enfermedades neurodegenerativas
Excitotoxicidad y EVC
• Posterior a la isquemia el glutamato se acumula en
la sinapsis
• Drejer, 1985, Rossi, 2000
• Se provoca gran estimulación del receptor NMDA
que provoca toxicidad
• Lipton, 2006; Lo 2003
Schematic of excitatory amino acid pathways and potential sites for pharmacological
intervention.
Muir K W , and Lees K R Stroke. 1995;26:503-513
Copyright © American Heart Association, Inc. All rights reserved.
Median values and quartiles (25% and 75%) of cerebrospinal fluid glutamate concentrations
in patients with stable (▴) and progressing (▪) ischemic stroke.
Dávalos A et al. Stroke. 1997;28:708-710
Copyright © American Heart Association, Inc. All rights reserved.
Diseño y desenlaces
• Tratamiento agudo vs crónico
o (Neuroprotección vs neurorreparación)
• Respuesta a tratamientos
combinados?
o Alteplasa
o Rehabilitación
DEFICIT A EVALUAR
• Motor?
• Cognitivo?
• Afasia?
• Mejoría vs no progresión
• Impacto sobre funcionalidad global y calidad de
vida
• Mortalidad y morbilidad
Agonistas colinérgicos
Efficacy and Tolerability of Donepezil in Vascular
Dementia
by Sandra Black, Gustavo C. Román, David S. Geldmacher, Stephen Salloway, Jane
Hecker, Alistair Burns, Carlos Perdomo, Dinesh Kumar, and Raymond Pratt
Stroke
Volume 34(10):2323-2330
October 1, 2003
Copyright © American Heart Association, Inc. All rights reserved.
Figure 2. ADAS-cog least squares (LS) mean change from baseline score in donepezil- and
placebo-treated patients.
Black S et al. Stroke. 2003;34:2323-2330
Copyright © American Heart Association, Inc. All rights reserved.
Figure 3. ADFACS least squares (LS) mean change from baseline score in donepezil- and
placebo-treated patients.
Black S et al. Stroke. 2003;34:2323-2330
Copyright © American Heart Association, Inc. All rights reserved.
icles
2007; 6: 782–92
Published Online
August 2, 2007
OI:10.1016/S14744422(07)70195-3
onandReaction
page749
General Internal
ivision of Health
esearch, Veterans
eater LosAngeles
CareSystem, and
of Psychiatry and
Sciences, Geffen
dicine, University
rnia LosAngeles,
Angeles, CA, USA
avirajan MD); and
of Psychiatry and
oral Sciences, and
Efficac
and me
Efficacy and adverse effectsof cholinesterase inhibitors
random
and memantine in vascular dementia: a meta-analysis
of
randomised controlled trials
Harish Kaviraja
Harish Kavirajan, Lon SSchneider
Summary
Background Cholinesterase inhibitors and memantine do not have regulatory approval in most of the world for
treatment of vascular dementia. A systematic review and meta-analysis was undertaken to assess the evidence for
efficacy and safety of cholinesterase inhibitors and memantine in vascular dementia.
Summary
Background
PublishedOnline treatment of
August 2, 2007 efficacy and
Findings Three donepezil, two galantamine, one rivastigmine, and two memantine trials, comprising 3093 patients
Lancet Neurol 2007;6:782–92
Methods PubMed, BIOSIS, International Pharmaceutical Abstracts, and Cochrane registries were searched for
randomised, placebo-controlled trials on cholinesterase inhibitors and memantine in patients with vascular dementia.
Trial methods, clinical characteristics, outcomes, and adverse events were extracted and checked. Meta-analytic
methods using fi xed-effects models were used to give summaries of each drug’s effects.
DOI:10.1016/S14744422(07)70195-3
on the study drugs and 2090 patients on placebo, met the selection criteria. Trials were of 6-month duration with
similar vascular dementia criteria and outcome measures. Cognitive effects on the Alzheimer’s Disease Assessment
scale were significant for all drugs, ranging from a –1· 10 point mean difference (95% CI –2· 15 to –0· 05) for
rivastigmine to –2· 17 for 10 mg daily donepezil (95% CI –2· 98 to –1· 35). Only 5 mg daily donepezil had an effect on
the Clinicians’ Global Impression of Change scale (odds ratio 1· 51 [95% CI 1· 11–2· 07]). No behavioural or functional
benefits were observed, except for a –0· 95 point difference (95% CI –1· 74 to –0· 16) with 10 mg daily donepezil on the
Alzheimer’s Disease Functional Assessment and Change Scale. Compared with placebo, more dropouts and adverse
SeeReflectionandReaction
page749
Methods Pu
randomised,
Donepezilo, galantamina, rivastigmina: beneficio en pruebas neuropsicológicas
Volume 41 Number 4, July/August 2004
Pages 525 — 534
Donepezil as an adjuvant to constraint-­
induced therapy for upper-­limb dysfunction
after stroke: An exploratory randomized
clinical trial
8/20/2014
Donepezil as an adjuvant to constraint-induced therapy for upper-limb dysfunction after stroke: An exploratory randomized clinical trial
Stephen E. Nadeau, M D;; Andrea L. Behrman, PhD;; Sandra E. Davis, PT;; Kimberly Reid, M S;;
Samuel S. Wu, PhD;; Brenda S. Stidham, RN;; Karen M . Helms, PharmD;; Leslie J. Gonzalez
Rothi, PhD
Brain Rehabilitation Research Center; Rehabilitation Outcomes Research Center; Geriatric Research,
Education
and Clinical Center; Pharmacy Service; and the Neurology Service, Malcom Randall Department of Veterans
Affairs Medical Center, Gainesville, FL; Department of Physical Therapy, College of Health Professions, and
Departments
of Neurology and Statistics, University of Florida College of Medicine, Gainesville, FL
Abstract — Donepezil, a primarily central acetylcholinesterase inhibitor, could potentiate learning in subjects with stroke by
amplifying cholinergic input to the cerebral cortex from the nucleus basalis of Meynert. We tested this possible adjuvant effect
of donepezil in a prospective randomized, double-blind, placebo-controlled, parallel-group study of 20 subjects 1 or more years
following stroke undergoing constraint-induced therapy (CIT) for upper-limb dysfunction. CIT had substantial and significant
effects on both primary outcome measures, the Wolf Motor Function Test (WMFT) and the Motor Activity Log (amount), and
all secondary measures, including the Box and Block Test, the Actual Amount of Use Test, the Fugl-Meyer Motor Scale-Upper
Extremity, and the Caregiver Strain Index. Subjects receiving donepezil achieved differential gains on the WMFT approaching
statistical significance (p = 0.067, corrected for multiple comparisons), but not on other measures. This study is inconclusive,
but a larger randomized controlled trial with adequate statistical power should be pursued because of the potential benefits of
the treatment to stroke survivors.
Key words: constraint-induced therapy, donepezil, hemiparesis, rehabilitation, stroke.
Abbreviations: AD = Alzheimer's disease, CIT = constraint-induced therapy, CSI = Caregiver Strain Index, GDS = Geriatric
ANTAGONISTAS NMDA
EVIDENCIAS CLÍNICAS
• Múltiples compuestos que han resultado tóxicos o
no eficaces
• No eficaces:
o Eliprodil
o Aptiganel
• Tóxicos
o Selfotel
• Davis, Vasc Med 1999
Selfotel in Acute I schemic Stroke: Possible Neurotoxic Effects of an NM DA Antagonist
Stephen M. Davis, Kennedy R. Lees, Gregory W. Albers, Hans Christoph Diener, Sabri
Markabi, Goeril Karlsson and John Norris
Stroke. 2000;31:347-354
doi: 10.1161/01.STR.31.2.347
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2000 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/31/2/347
Entusiasmo sobre
antagonistas NMDA
MEMANTINA y Mg
Memantina y Mg:
Mecanismo de acción
M emantine Enhances Recovery From Stroke
Héctor E. López-Valdés, Andrew N. Clarkson, Yan Ao, Andrew C. Charles, Stanley Thomas
Carmichael, Michael V. Sofroniew and Kevin C. Brennan
Stroke. published online June 17, 2014;
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2014 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/early/2014/06/17/STROKEAHA.113.004476
Data Supplement (unedited) at:
http://stroke.ahajournals.org/content/suppl/2014/06/17/STROKEAHA.113.004476.DC1.html
Aumento en representación sensitiva cortical y expresión de
BNDF (Brain derived neurotrofic factor)
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Author'spersonal copy
Neuropsychol Rev (2011) 21:302–317
DOI 10.1007/s11065-011-9177-7
REVIEW
Dr ug Ther apy of Post-Stroke Aphasia: A Review
of Cur rent Evidence
Marcelo L . Ber thier &Fr iedemann Pulver müller &
Guadalupe Dávila &Natalia García Casares &
Antonio Gutiér rez
Author'spersonal
Neuropsychol Rev (2011) 21:302–317
DOI 10.1007/s11065-011-9177-7
Received: 27 June 2011 / Accepted: 27 July 2011 / Published online: 16 August 2011
# Springer Science+Business Media, LLC 2011
REVIEW
Abstr act This review considers the role of drug therapy in
the treatment of post-stroke aphasia, the evidence for
efficacy of different agents, and the theory-based explanations of drug-related benefits for aphasia rehabilitation.
Pharmacological interventions modulating stroke-induced
disruption of diverse neurotransmitters may improve language and communication deficits in aphasic patients
through facilitation of brain plasticity and long-term
potentiation. However, benefits are not evident for all
compounds and refinement in clinical trial designs is
required. Some pharmacological trials have failed because
drug treatment was not combined with speech-language
therapy, while other trials combining drugs with intensive
model-driven therapies also failed probably because of
short-trial duration, inadequate sample selection, or lack of
drug action. Preliminary data reveals that combining
neuroscience-based intensive aphasia techniques (constraint-
induced aphasia therapy) and drugs acting on cholinergic and
glutamatergic neurotransmitter systems are associated with
better outcomes than other strategies and long-term maintenanceof benefits. Although further studiesareneeded, current
state of the evidence suggests that drug therapy may play a
key role in the treatment of post-stroke aphasia.
Drug Therapy of Post-Stroke Aphasia:
of Current
Evidence
INTERPRETATION: Both memantine and CIAT alone
improved
aphasia severity,
but best outcomes were achieved combining memantine with CIAT.
Marcelo L. Berthier &Friedemann Pulvermüller &
. Aphasia
. Aphasia
KGuadalupe
eywor
Stroke
aphasia
recovery
Beneficial effects of memantine and CIAT persisted
onds. long-term
follow-up.
Dávila
&Natalia
García
Casares
&
M. L. Berthier (* ) : G. Dávila : N. G. Casares
Unit of Cognitive Neurology and Aphasia,
Centro de Investigaciones Médico­Sanitarias (CIMES),
treatment
Pharmacological treatment
Antonio Gutiérrez
Acronyms
CAL
Communicative Activity Log
CIAT
Constraint-induced aphasia therapy
Received: 27Constraint-induced
June 2011 /Accepted: language
27 July 2011
/Published online: 16 August 201
CILT
therapy
# Springer Science+Business Media, LLC 2011
CPAP
Continuous positive airway pressure
fMRI
Functional magnetic resonance imaging
NMDA
N-methyl-D-aspartate
Abstr act This
review considers the role of drug therapy in
induced
PSA
Post-stroke
aphasia aphasia, the evidence for
the treatment
of post-stroke
glutama
WAB
efficacy of Western
differentAphasia
agents, Battery
and the theory-based explanbetter o
WAB-AQ Western Aphasia Battery-Aphasia Quotient
ations of drug-related benefits for aphasia rehabilitation.
nanceof
Field Administration of Stroke Treatment –
Magnesium (FAST-MAG) Trial
• Placebo-controlled, double-blind, randomized
• Multicenter, single region
» 59 hospitals, Los Angeles and Orange Counties
• 4 gm Mg field, 16 gm Mg maintenance x 24h
• 1700 patients, 1st patient Jan 2005
• Primary endpoint: Rankin Scale shift
Resultados
• mRs a 90 días similar en el grupo placebo y Mg
• 75% de los pacientes iniciaron tratamiento en la
“hora dorada”
• Primer estudio de tratamiento prehospitalario
• Nueva oportunidad terapéutica
CONCLUSIÓN
• Pobres resultados en neuroprotección
• Posible beneficio en neurorreparación
• Definir desenlaces clínicos relevantes
GRACIAS