neuronal protective agents

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



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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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ZK200775 AMPA receptor antagonist

Trials halted because of excessive

sedation at therapeutic levels


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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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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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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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MK-801 (dizocilpine) NMDA receptor blocker

No current clinical development for

stroke


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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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ACEA 1021 (licostinel) Glycine site antagonist

Trials halted because results from

Phase I trial, revealed ACEA 1021crystals in subjects urine


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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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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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GV150526 GAIN Americas

Same criteria as International

N=561

Preliminary result: no effect


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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



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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


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