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Neuronal protective agents

Andrew 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 cont’d 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 cont’d 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, randomized controlled trial with 50 patients

Inclusion: CT, SPECT, and nimodipine within 12 hours of symptoms

30 mg po 6h for 14 days Primary outcome: SPECT 24hrs and 3

months later; modified Canadian Neurological Scale; and CT and Barthel stroke index at 3 months

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Nimodipine

Results: no change in perfusion volumes at 3 months Non-nutritional reperfusion in

nimodipine 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 Acute Ischemic Hemispheric Stroke Stroke 1994;25:1348-1353

Multicentered, n=350 Acute, hemispheric stroke, and

within 48 hours of onset 120mg nimodipine po/day

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Nimodipine

Outcome: Rankin score in 12 months

Results: higher case fatality at 1 and 3 months in nimodipine group (p=.004, and p=.03), which is not statistically significant at 1 year

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Nimodipine

Double-blind Study of Nimodipine in Non-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 4

months Results: no difference

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Nimodipine

Nimodipine in Acute Ischemic Stroke Acta Neurol Scand 1989

Oct;80(4):282-6 N=4, admitted within 12 hours 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 Ischemic Cerebral Infarction Stroke 1990 Jul;21(7):1023-8

Multicentred, n=164 Outcome: Mathew scale and mortality at

28 days Result: no difference but post hoc sub-

group analysis of patients with better baseline score (Mathew>65) had better outcome in nimodipine group

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Nimodipine

Controlled Trial of Nimodipine in Acute Ischemic Stroke N Engl J Med 1988 Jan 28;318(4):203-7

Multicentred, n=186, presentation within 12 hours symptom onset

Outcome: Mathew scale and death at 28 days and six months

Results: in nimodipine group: decreased mortality in men at 28 days and improved and better neurological status at 6 months

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Nimodipine

Very Early Nimodipine Use in Stroke (VENUS) Presented at 24th International Joint

Conference on Stroke and Cerebral Circulation

N=434, present within 6 hours, and receive nimodipine for 10 days

Outcome: death and Rankin score at 10 days and 3 months

Results: no difference in outcome, and trial was terminated early

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Nimodipine

Randomized, Double-Blind, Placebo-Controlled Trial of Nimodipine in Acute Stroke Lancet 1990 Nov 17;336(8725):1205-9

Multicentred, n=1215 Within 48 hours, and previous independent

functioning Outcome: 6 months independence, as

defined of over 60 on Barthel index Results: no difference at 6 months; delayed

recovery in nimodipine group at 3 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, and

motor strength up to 21 days Results: no difference overall but post-

hoc subgroup analysis showed less worsening in nimodipine group if given within 18 hours and pretreatment scan was 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 24 hours, 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 or CNS

side effects

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Antioxidants – Tirilazad (Freedox) Lipid peroxidation inhibitor Randomized Trial of Tirilazad Mesylate

in Acute Stroke (RANTTAS) Stroke 1996 Sep;27(9):1453-1458

Multicentred, n=556, symptoms within 6 hours

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 Tirilazad in Acute Stroke (RANTAS II) Stroke 1998;29:1256-1257

Multicentred, n=126 Higher dosage than RANTTAS: males

given 10 mg/kg/d for 2 days and females 15 mg/kg/d for 1 day and then 12 mg/kg/d

Results: trial discontinued after 126 patients because of safety concerns arising 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):21-28

N=1360, multicentred Within 12 hours, no major respiratory,

renal, hepatic disorder Outcome: Barthel index at 3 months Result: no difference; may cause

sedation; possible benefit in hemorrhagic stroke

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Clomethiazole

Clomethiazole in Acute Stroke Study in Ischemic, Hemorrhagic, and 47 tPA-treated patients

Patients within 12 hours with large ischemic infarcts (n=1200), patients who received tPA (n=100), and with hemorrhagic infarct (n=200)

Outcome: for ischemic infarcts, functional recovery as defined by >60 on Barthel index; for other groups, assess safety

Ongoing trial: results not published

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Glutamate antagonists – YM872 AMPA receptor antagonist Only Phase I completed,

demonstrating safety in elderly subjects

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 Selfotel

treatment (ASSIST) Stroke 2000;31(2):347-54

Multicentered, RCT, n=567 Presented within 6 hours onset, and

hemispheric stroke 1.5 mg/kg iv Selfotel over 5 minutes Outcome: Barthel index at 3 months Results: no difference. Higher mortality in

selfotel group at 30 days (p<.05), and more behavioral effects

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Glutamate antagonists – Aptiganel (Cerestat) NMDA channel blocker Phase III trial of Cerestat in Acute Stroke

Patients Not published

Multicentred trial of ischemic stroke within 6 hours

Outcome: modified Rankin at 3 months Interim analysis of 628 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 of CP-101,606 in

subjects with a severe traumatic head injury or spontaneous intracerebral hemorrhage Ann NY Acad Sci 1999;890:51-8

N=30 (20 with head injury), given iv infusion, initially .75mg/kg/hr; infusion given for 2, 24, and 72 hours

Outcome: GCS at 6 months Patients with infusions for 24 and 72 hours

better GCS at 6 months

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Glutamate antagonists 0 CP-101,606 A double blind, placebo controlled study

of the safety, tolerability, and pharmacokinetics of CP-101,606 in patients with a mild or moderate traumatic brain injury Ann NY Acad Sci 1999;890:42-50

Infusion began within 12 hours: .75 mg/kg/hr for 2 hours then .37 mg/kg/hr for 22-70 hrs

No major adverse reactions and tolerated well

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Glutamate antagonists - dextrorphan NMDA channel blocker Safety, tolerability, and pharmacokinetics

of the NMDA antagonist dextrorphan in patients 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 followed by 50-75 mg/hr for 11 hours) were better tolerated and produced plasma levels which may be neuroprotective

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Magnesium

Blockers voltage gated calcium channels and NMDA receptors

Intravenous magnesium efficacy in stroke (IMAGES) began after safety study revealed no incidence of adverse effects

Recruiting 2700 patients, within 12 hours

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 2 has demonstrated the safe dosage, 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 1021 crystals in subjects’ urine

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Glutamate antagonists – GV150526 (gavestinel) Glycine site antagonist Glycine antagonist for Neuroprotection

(GAIN 1) and GAIN 2 Presented, not published

Multicentred, patients within 12 hours 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; within 6 hours of moderate

stroke. 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 of

fibroblast growth factor, n=302 Outcome: Rankin scale 3 months Significantly worse outcome in

growth factor group

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Leukocyte adhesion inhibitor – Anti ICAM 1 antibody (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 6 hours 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 adhesion molecule

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 II trial suggested benefit (Stroke 1997;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 trial

followed Phase 2, which suggested benefit in people <70.

Presenting within 6 hours Outcome: Barthel scale and GCS at 12

weeks Results: no difference

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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 or 2000 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 24 hours, and

receive drug for 6 wks. Outcome: gain of 7 points on NIHSS in

12 weeks Result: no difference in primary endpoint,

but the secondary endpoint of complete/near-complete recovery was higher (p<.05) in citicoline group

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Serotonin agonist – Bay x 3072 (repinotan) Bayer Randomized Acute Ischemia

Neuroprotectant Study Multicentre, n=120 (Phase 2) Within 6 hours 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 of iv fosphenytoin in patients with acute ischemic stroke

N=462, treatment within 4 hours Outcome: Rankin scale 3 months Results: no difference