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8/3/2019 Neuronal Protective Agents
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Neuronal
protective agentsAndrew Nataraj
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Categories
Calcium Channel blockers
Nimodipine
Flunarizine
Calcium chelators
DP-b99
Free radical scavengers
Ebselen
Tiralazad
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Categories
GABA agonists
Clomethiazole
Glutamate antagonists AMPA antagonists:
GYKI 52466
NBQX
YM90K
YM872 ZK-200775
Kainate antagonists:
SYM 2081
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Categories
Glutamate anatgonists contd
NMDA antagonists
Competitive antagonists:
CGS 19755 (Selfotel)
NMDA channel blockers
Aptiganel (Cerestat)
CP 101,606
Dextrorphan
Dextromethorphan Magnesium
Memantine
MK 801
Remacemide
NPS 1506
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Caetgories
Glutamate antagonists contd
Polyamine site antagonists
Eliprodil
Ifenprodil
Growth factors
Fibroblast growth factor
Leukocyte adhesion inhibitors
Anti-ICAM antibody (Enlimomab) Hu23F2G
Nitric oxide inhibitor
Lubeluzole
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Categories
Opioid antagonists
Naloxone
Nalmefene
Phosphatidylcholine precursor
Citicholine (CDP-choline)
Serotonin agonist BAYX 3072
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Categories
Potassium channel openers
Sodium channel blockers
Fosphenytoin
Lubeluzole
619C89
Mechanism uncertain Piracetam
lubeluzole
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Nimodipine (Nimotop) Blocks L-type calcium channels
Approved for treatment of
subarachnoid hemorrhage
Several studies regarding
nimodipine in stroke, with some
confliciting results
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Nimodipine Nimodipine and Perfusion changes after
stroke (NIMPAS)
Stroke 1999;30:1417-1423
Prospective, double blind, randomizedcontrolled trial with 50 patients
Inclusion: CT, SPECT, and nimodipinewithin 12hours of symptoms
30 mg po 6h for 14 days Primary outcome: SPECT 24hrs and 3
months later; modified CanadianNeurological Scale; and CT and Barthelstroke index at 3 months
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Nimodipine Results: no change in perfusion
volumes at 3 months
Non-nutritional reperfusion innimodipine group was associated
with worse functional outcome at 3
months (p=.06)
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Nimodipine Randomized, Double blind,
placebo-controlled trial of
nimodipine in AcuteIschemicHemispheric Stroke
Stroke 1994;25:1348-1353
Multicentered, n=350
Acute, hemispheric stroke, andwithin 48 hours of onset
120mg nimodipine po/day
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Nimodipine Outcome: Rankin score in 12
months
Results: higher case fatality at 1and 3 months in nimodipine group
(p=.004, and p=.03), which is not
statistically significant at 1 year
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NimodipineDouble-blind Study of Nimodipine inNon-Severe Stroke
Eur Neurol 1990;30(1):23-6 N=60, presented within 48 hours,
and Mathew scale 50-75
30mg po qid
Outcome: Mathew scale at 4months
Results: no difference
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Nimodipine Nimodipine in Acute Ischemic
Stroke
Acta Neurol Scand 1989Oct;80(4):282-6
N=4, admitted within 12hours
40 mg tid po
Outcome: Mathew scale to day 28 Higher rate of improvement in
nimodipine group
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Nimodipine Placebo-controlled Trial of Nimodipine in
the Treatment of Acute IschemicCerebral Infarction
Stroke 1990 Jul;21(7):1023-8
Multicentred, n=164
Outcome: Mathew scale and mortality at28 days
Result: no difference but post hoc sub-group analysis of patients with betterbaseline score (Mathew>65) had betteroutcome in nimodipine group
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Nimodipine
Controlled Trial of Nimodipine in AcuteIschemic Stroke
N Engl J Med 1988 Jan 28;318(4):203-7
Multicentred, n=186, presentation within12hours symptom onset
Outcome: Mathew scale and death at 28days and six months
Results: in nimodipine group: decreasedmortality in men at 28 days andimproved and better neurological statusat 6 months
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Nimodipine
Very Early Nimodipine Use in Stroke(VENUS)
Presented at 24thInternational Joint
Conference on Stroke and CerebralCirculation
N=434, present within 6hours, andreceive nimodipine for 10 days
Outcome: death and Rankin score at 10days and 3 months
Results: no difference in outcome, andtrial was terminated early
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Nimodipine
Randomized, Double-Blind, Placebo-Controlled Trial of Nimodipine in AcuteStroke
Lancet 1990 Nov 17;336(8725):1205-9
Multicentred, n=1215
Within 48 hours, and previousindependent functioning
Outcome: 6 months independence, asdefined of over60 on Barthel index
Results: no difference at 6 months;delayed recovery in nimodipine group at3 weeks.
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Nimodipine
American Nimodipine Study
Stroke 1992 Apr;23(4):615
Multicentred, n=1064
Ischemic stroke within 48 hours
Primary outcome: Toronto scale, andmotor strength up to 21 days
Results: no difference overall but post-
hoc subgroup analysis showed lessworsening in nimodipine group if givenwithin 18 hours and pretreatment scanwas negative (p=.005)
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Calcium channel blocker
- flunarizine Flunarizine in stroke treatment (FIST)
Acta Neurol Scand 1996:93(1) 56-60
Multicentered, n=331 Ischemic stroke in MCA territory and
within 24hours, GCS>3
Outcome: modified Rankin score,
mortality and modified Barthel index
Result: no difference
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Calcium chelators DP-
b99 Membrane activated calcium
chelator
Phase I trial only: no CV orCNSside effects
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Antioxidants Tirilazad
(Freedox) Lipid peroxidation inhibitor
Randomized Trial of Tirilazad Mesylatein Acute Stroke (RANTTAS)
Stroke 1996 Sep;27(9):1453-1458
Multicentred, n=556, symptoms within 6hours
150mg tirilazad iv and 1.5mg/kg q6h iv
for 11 more doses Outcome: GCS and Barthel index at 3
months
Results: no difference
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Tirilazad
Randomized Trial of High Dose Tirilazadin Acute Stroke (RANTAS II)
Stroke 1998;29:1256-1257
Multicentred, n=126
Higher dosage than RANTTAS: malesgiven 10 mg/kg/d for2 days and females15 mg/kg/d for 1 day and then 12
mg/kg/d Results: trial discontinued after 126
patients because of safety concernsarising from a trial in Europe
Analysis of these patients showed no
difference
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GABA agonists -
clomethiazole Clomethiazole Acute Stroke Study
(CLASS)
Stroke 1999;30(1):
21-2
8 N=1360, multicentred
Within 12hours, no major respiratory,
renal, hepatic disorder
Outcome: Bart
hel index at
3mont
hs
Result: no difference; may cause
sedation; possible benefit in hemorrhagic
stroke
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Clomethiazole
Clomethiazole in Acute Stroke Study inIschemic, Hemorrhagic, and 47 tPA-treated patients
Patients within 12hours with largeischemic infarcts (n=1200), patients whoreceived tPA (n=100), and withhemorrhagic infarct (n=200)
Outcome: for ischemic infarcts,functional recovery as defined by >60 onBarthel index; for other groups, assesssafety
Ongoing trial: results not published
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Glutamate antagonists
YM872 AMPA receptor antagonist
Only Phase I completed,
demonstrating safety in elderlysubjects
Others ongoing
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Glutamate antagonists
ZK200775 AMPA receptor antagonist
Trials halted because of excessive
sedation at therapeutic levels
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Glutamate antagonists
CGS 19755 (Selfotel) Competitive NMDA receptor antagonist
Acute Stroke Studies involving Selfoteltreatment (ASSIST)
Stroke 2000;31(2):347-54
Multicentered, RCT, n=567
Presented within 6hours onset, andhemispheric stroke
1.5 mg/kg iv Selfotel over 5 minutes Outcome: Barthel index at 3 months
Results: no difference. Higher mortalityin selfotel group at 30 days (p
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Glutamate antagonists
Aptiganel (Cerestat) NMDA channel blocker
Phase III trial ofCerestat in Acute Stroke
Patients Not published
Multicentred trial of ischemic stroke
within 6hours
Outcome: modified Rankin at
3mont
hs
Interim analysis of628 patients
concluded that continuation was not
justified.
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Glutamate antagonists
CP-101,606 NMDA channel blocker
Selective for NR2B subunit
An open-label study ofC
P-101,606
insubjects with a severe traumatic headinjury or spontaneous intracerebralhemorrhage
Ann NY Acad Sci 1999;890:51-8
N=30 (20 withhead injury), given ivinfusion, initially .75mg/kg/hr; infusiongiven for2, 24, and 72hours
Outcome: GCS at 6 months
Patients with infusions for24 and 72
hours betterGCS at 6 months
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Glutamate antagonists 0
CP-101,606 A double blind, placebo controlled study
of the safety, tolerability, andpharmacokinetics ofCP-101,606 in
patients with a mild or moderatetraumatic brain injury
Ann NY Acad Sci 1999;890:42-50
Infusion began within 12hours: .75mg/kg/hr for2hours then .37 mg/kg/hrfor22-70 hrs
No major adverse reactions andtolerated well
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Glutamate antagonists -
dextrorphan NMDA channel blocker
Safety, tolerability, and pharmacokineticsof the NMDA antagonist dextrorphan inpatients with acute stroke Stroke 1995;26(2):254-58
N=22 given loading dose and infusion
Higher doses were not tolerated, but
lower doses (145-180 loading followedby 50-75 mg/hr for 11 hours) were bettertolerated and produced plasma levelswhich may be neuroprotective
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Magnesium
Blockers voltage gated calciumchannels and NMDA receptors
Intravenous magnesium efficacy instroke (IMAGES) began aftersafety study revealed no incidenceof adverse effects
Recruiting2700 patients, wit
hin 1
2hours
Multicentred, RCT
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Glutamate antagonists
MK-801 (dizocilpine) NMDA receptor blocker
No current clinical development for
stroke
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Glutamate antagonists
NPS 1506 NMDA channel blocker
Phase I trials are on hold for
financial reasons
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Glutamate antagonists -
remacemide NMDA receptor blocker
No trials in acute ischemic stroke
Phase 2has demonstrated the safedosage, but not enough power to
comment on neurological status
Possible neuroprotective benefit, as
shown in patients neuropsychological
outcome after cardiac surgery (p=.028) Stroke 1998;29(11):2357-62
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Glutamate antagonists
ACEA 1021 (licostinel) Glycine site antagonist
Trials halted because results from
Phase I trial, revealed ACEA 1021crystals in subjects urine
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Glutamate antagonists
GV150526 (gavestinel) Glycine site antagonist
Glycine antagonist for Neuroprotection
(GAIN 1) and
GAIN2
Presented, not published
Multicentred, patients within 12hours of
symptom onset; intended to assess
safety profile
Outcome: Barthel index day 7 and 4
weeks
Results: no increase in adverse events
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Glutamate antagonists
GV150526 GAIN International
Not published
N=1804; wit
hin6
hours of moderatestroke. Patients functionally independent
before stroke
RCT, multicentred
Outcome: Barthel index 3 months and
mortality
Results: no significant difference
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Glutamate antagonists
GV150526 GAIN Americas
Same criteria as International
N=561
Preliminary result: no effect
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Glutamate antagonists
SL 82-0715 (eliprodil) Polyamine site antagonist
No demonstrated efficacy
Phase 3 trial discontinued
Results not reported
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Growth factors
fibroblast growth factor Phase III trial halted because of
safety issues after interim analysis
Patients received 5-10mg offibroblast growth factor, n=302
Outcome: Rankin scale 3 months
Significantly worse outcome in
growth factor group
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Leukocyte adhesioninhibitor Anti ICAM 1antibody (enlimomab) Monoclonal antibody against intercellular
adhesion molecule ICAM 1, which is
required for leukoctye attachment and
migration
Enlimomab Actue Stroke Trial (EAST)
Neurology 1997;48(Supp) A270
N=625, within 6hours ischemic stroke
Outcome: modified Rankin scale 90 days
Results: mortality and Rankin score
worse in enlimomab group (p=.004)
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Leukoctye adhesion
inhibitor Hu23F2G Leukarrest
Monoclonal antibody against
neutrophil CD11/CD18 adhesionmolecule
Hu23F2G Phase 3 stroke trial
(HALT) stopped because interim
analysis showed no success
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Nitric oxide inhibitor -
lubeluzole Lubeluzole in ischemic stroke
Phase III multicentred RCT done after
Phase
IItrial suggested benefit (Stroke1997;28:2338-2346)
0-8 hours from onset, exclude severe
stroke
Outcome: Barthel index at 12 weeks
Results: no difference
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Opioid antagonists
nalmefene (Cervene) Selective kappa opiate receptor
antagonist
Cervene in acute ischemic stroke
Stroke 2000;31(6):1234-9
Multicentred, n=368. This Phase 3 trialfollowed Phase 2, which suggestedbenefit in people
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Phosphatidylcholine
precursor - citicoline Acts as membrane stabilizer
Citicoline stroke study
Neurology 1997;49(3):671-8 Multicentered, n=259
Randomized to doses of 500 mg/d,1000 mg/d or2000 mg/d
Outcome: Barthel index 12 weeks Result: better outcome in the
500mg and 2000mg groups.
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Phosphatidylycholine
precursors - citicoline Phase III trial of citicoline 2000mg vs.
placebo
Multicentred trial, n=899
Patients present within 24hours, andreceive drug for6 wks.
Outcome: gain of 7 points on NIHSS in12 weeks
Result: no difference in primary endpoint,but the secondary endpoint ofcomplete/near-complete recovery washigher (p
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Serotonin agonist Bay
x 3072 (repinotan) Bayer Randomized Acute Ischemia
Neuroprotectant Study
Multicentre, n=120 (Phase 2) Within 6hours
Outcome: NIHSS at 4 weeks
Results not published
Phase 3 ongoing
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Sodium channel
blockers - fosphenytoin Pro-drug of phenytoin
Phase 3 trial: Multicentre study to
evaluate the safety and efficacy ofiv fosphenytoin in patients with
acute ischemic stroke
N=462, treatment within 4hours
Outcome: Rankin scale 3 months
Results: no difference
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