Clinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing?

doi:10.1016/S0166-2236(99)01463-0

Trends in Neurosciences

Volume 22, Issue 12, 1 December 1999, Pages 535-540

https://doi.org/10.1016/S0166-2236(99)01463-0 Get rights and content

Abstract

Ischaemic stroke is a leading cause of death and long-lasting disability. Several neuroprotective drugs have been developed that have the potential to limit ischaemic brain damage and improve outcome for patients. While promising results with these drugs have been achieved in animal stroke models, all Phase III trials conducted so far indicate that these drugs have failed to live up to their promise. Despite the limits of animal models, which cannot mimic the clinical situation, the disappointing results of neuroprotective trials might largely be due to methodological problems. Future trials with neuroprotective drugs should be performed in stroke (care) units, after sufficient information regarding therapeutic time window, dosage, duration of therapy and safety has been gathered from pilot studies, and a better selection of target patients has been made. Much of this information can now be obtained by techniques that visualize the penumbra, such as combined diffusion-weighted and perfusion MRI. Consideration should also be given to clinical trials with well-designed combinations of treatments.

Section snippets

Na⁺-channel blockers

The anticonvulsant phenytoin blocks voltage-dependent Na⁺ channels and reduces infarct size in both permanent and reperfusion models of focal brain ischaemia in rodents24, 25. Fosphenytoin is a prodrug of phenytoin that has been evaluated in a Phase III trial. Enrolment was halted after 462 patients had been included because no differences in primary or secondary endpoints were found in an interim analysis².

Ca²⁺-channel blockers

One obvious treatment strategy for stroke involves the regulation of Ca²⁺ entry into the cell using inhibitors of voltage-sensitive Ca²⁺ channels. Nimodipine is an inhibitor of L-type Ca²⁺ channels, whereas flunarizine mainly acts as a T-type Ca²⁺-channel blocker²⁶. Both these compounds can reduce infarct size when administered shortly after permanent and transient focal cerebral ischaemia²⁶. However, their potency is less than that of glutamate-receptor antagonists. Nimodipine has been studied

Glutamate inhibition or GABA stimulation

Inhibitors of glutamate receptors, particularly those that block NMDA receptors, can reduce infarction volume and neurological deficits in permanent and reperfusion models of focal cerebral ischaemia²⁸. The use of several NMDA-receptor antagonists was discontinued in Phase I and Phase II studies because of unacceptable adverse effects. The major problems with these compounds are psychomimetic effects (agitation, hallucinations, paranoia and delirium), sedation, catatonia and concerns about

NO-pathway inhibitors and free-radical scavengers

The neuroprotective effects of lubeluzole can be explained, at least partially, by a downregulation of the NO synthase (NOS) pathway, which reduces NO-related neurotoxicity³³. In a small Phase II trial, a dose of 7.5 mg lubeluzole given within 6 h of the first symptoms, followed by 10 mg per day for five days, was associated with reduced mortality. A double-dose regimen, which yielded a plasma concentration equivalent to the levels associated with neuroprotection in rats, was associated with

Drugs that mainly act at the cell membrane

In preclinical studies, the ganglioside, GM1, conferred protection against ischaemic and excitotoxic insults³⁸. However, two major Phase III trials produced negative results19, 20. Because of concerns regarding a possible association with the development of Guillain–Barré syndrome³⁰, GM1-ganglioside product licences have been suspended.

After a number of small inconclusive clinical trials with citicholine (cytidine-5-diphosphocholine or CDP-choline), a multicentre dose-finding study in the USA

Anti-inflammatory agents

Within hours, endothelial adhesion molecule 1 (ICAM1) levels are increased in the zone of focal cerebral ischaemia, which allows an influx of white cells into the ischaemic brain area. Cytokines released from the invaded white cells contribute to brain-tissue damage. ICAM1 antibodies reduced infarct volume in rats, only when the model included reperfusion, but not with permanent middle-cerebral-artery occlusion⁴¹. Enlimomab, a murine monoclonal antibody against ICAM1, has been studied in a

Animal models

Because all the Phase III stroke trials with neuroprotective drugs have failed to live up to their promise, one could argue that the animal models that have been used to test these substances have no predictive value. Focal ischaemia models can be broadly categorized into two types: permanent and reversible⁴². In patients, both types of focal brain ischaemia can occur43, 44. Both forms of insult can produce a potentially salvageable penumbra. In the transient-occlusion model, reperfusion injury

Future prospects

In view of the fact that it is not possible to translate from the animal model to the clinical situation, it appears that the overall disappointing results of clinical trials that have accumulated over the past decade are probably due to protocol and dosage problems. More attention should be paid to properly conducted Phase II trials in order to obtain sufficient information regarding therapeutic time window, dosage, duration of therapy and safety. In small sample sizes of patients, this

Combination therapy

All neuroprotective agents studied so far target a specific pathway of the ischaemic cascade. It is evident that the administration of either an NMDA-receptor antagonist or a voltage-dependent Ca²⁺-channel blocker will not be able to control excessive neuronal Ca²⁺ accumulation completely. Although these compounds can reduce infarct size in animal models, we should not expect that any single drug that interferes with a specific event in the ischaemic cascade will have a large clinical impact.

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Trends in Neurosciences

Perspectives on diseaseClinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing?

Abstract

Section snippets

Na+-channel blockers

Ca2+-channel blockers

Glutamate inhibition or GABA stimulation

NO-pathway inhibitors and free-radical scavengers

Drugs that mainly act at the cell membrane

Anti-inflammatory agents

Animal models

Future prospects

Combination therapy

Eur. Neurol.

Lancet

Stroke

Stroke

Neurodegeneration

Biochem. Pharmacol.

Cerebrovasc. Dis.

Brain Res.

J. Cereb. Blood Flow Metab.

Stroke

Cerebrovasc. Dis.

Stroke

Neurology

Stroke

Cerebrovasc. Dis.

Cerebrovasc. Dis.

Cerebrovasc. Dis.

Cerebrovasc. Dis.

Acta Neurol. Scand.

Lancet

Stroke

Cerebrovasc. Dis.

Stroke

Stroke

Stroke

Stroke

Stroke

Stroke

Stroke

Stroke

Cerebrovasc. Dis.

Neurosci. Lett.

Chung Hua I Hsueh Tsa Chih Taipei

Cerebrovasc. Dis.

Perspectives on disease
Clinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing?

Na⁺-channel blockers

Ca²⁺-channel blockers