Last month's publication of negative results from a clinical trial of a neuroprotective drug reinforces the growing belief that this class of drugs may never prove effective in the treatment of stroke despite their initial promise.

Although the NMDA (N-methyl-d-aspartate) receptor blocker, Aptiganel, improves outcomes in animal models of focal brain ischemia, a multicenter trial in humans showed that when administered within six hours of onset of symptoms of stroke, the drug did not improve patient outcomes and may even be harmful (JAMA 286, 2673; 2001). The trial was stopped in 1997.

Genentech's tissue plasminogen activator (TPA), is presently the only approved treatment for stroke, and works by dissolving blood clots in the brain. TPA must be administered within three hours of symptom onset, increases the risk of brain hemorrhage, and only patients in whom cerebral hemorrhage has been excluded are eligible for treatment.

The neuroprotectives were designed to ameliorate the damage to brain cells, which follows a cerebral infarct. Aptiganel (Cerestat)—developed by the UK biotechnology company CeNeS in conjunction with the German pharmaceutical manufacturer Boehringer Ingleheim—blocks the effects of the excitatory neurotransmitter glutamate at NMDA receptors. Glutamate worsens the initial ischemic injury by causing an influx of sodium and calcium into neurons.

Aptiganel was tested in 628 patients in 156 centers in the US, Canada, Australia, South Africa, England and Scotland. However, at seven days after treatment, placebo-treated patients showed better neurological improvement than high-dose aptiganel patients and the mortality rate was higher in aptiganel-treated patients.

Aptiganel is one in a long list of neuroprotectives that have not lived up to their preclinical promise. In recent years scientists have abandoned a number of similar products at late stages of development, in cluding Bristol–Myers Squibb's potassium channel agonist, MaxiPost, AstraZeneca's GABA modulator, Zendra and GlaxoWellcome's gavestinel, another NMDA blocker.

The continuing disappointments raise questions over where to go next in stroke treatment. Is there a future for these agents? “Absolutely yes,” says James Grotta, head of the stroke protection program at the University of Texas, Houston. The main problem is treating the patient quickly enough. These drugs were effective in animals when given within a few hours of stroke onset, but in the clinic, the time lapse was a more realistic three to six hours. The researchers in the Cerestat study believe this was the most likely explanation for its failure.

And there other potential reasons for the collective failure of the neuroprotectives. One major consideration, says Grotta, is that trials have thus far only looked at the neuroprotectives as monotherapies, and not in combination with TPA. Therefore the arteries supplying the damaged area is still blocked, and “this limits the amount of drug we can get to the damaged tissue.” Grotta also believes the drugs tested so far have not been potent enough.

Whatever the reasons, the brain has peculiarities of its own that need to be taken into account in the development of neuroprotectives. It is more susceptible to ischemic damage than other organs—giving a shorter therapeutic window—and, unlike the heart, it easily bleeds after injury. “Don't forget that 'protective' therapy has not been successful in other organ systems, such as the heart, either,” says Grotta.