THERAPY

Latest products of neural research

-Sean Henahan-

Years of painstaking basic research into the workings of the brain may now begin to bear fruit as clinical data become available for several new agents. These have been developed to prevent or reduce the damage associated with stroke, head trauma and related problems, reported researchers at the 5th International Symposium on Pharmacology of Cerebral Ischemia, held recently in Marburg, Germany.

In recent years, laboratory researchers have gained considerable insight into the acute neurotoxic molecular processes that accompany traumatic brain injury and related conditions.

Indeed, clinical neurologists are rejecting the old orthodoxy that the brain is incapable of repairing itself, in favour of the concept of neuronal plasticity. Furthermore, there is now hope that these natural healing mechanisms of the brain can be exploited by pharmaceutical researchers.

The drugs under development for these indications function either by stimulating production of neurochem­ical reparative molecules, or by inhibiting the production of chemicals associated with neuronal destruction. Since most of the damage to the brain occurs within hours of injury, researchers are concentrating on drugs active in the acute phase of trauma.

Two agents close to approval One of the agents furthest along in clinical trials is

polyethylene glycol-superoxide dismutase [PEG­SOD!. It 'scavenges' free oxygen radicals - molecules believed to playa significant role in the destruction of neuronal processes in the acute stage of brain trauma.

Conjugating the superoxide dismutase component with polyethylene glycol, commonly known as antifreeze. extends the drug's half-life from a few minutes to 5 days, explained Dr David Marmarou, from the Medical College of Virginia, US.

Recent clinical experience with PEG-SOD in a randomized, placebo-controlled trial of 104 patients with traumatic brain injury showed a survival advantage in patients receiving PEG-SOD. *

' We've established that the drug is safe, and we can see a trend in favor of efficacy. with no significant adverse effects. Two larger trials have since begun. so. by the end of the year, we should know whether PEG-SOD is effective in the treatment of severe head injury. '. said Dr Marmarou.

Tirilazad mesylate [Freedox®; UpjohnJ. a lazaroid. is also well along in clinical trials. It appears to exert cyto­protective and positive vascular effects on the brain, and is being investigated in clinical studies of subarachnoid haemorrhage, traumatic brain injury and stroke.

Dr B Musch, from Brussels, Belgium, reviewed data from a study involving 1023 patients with aneurysmal subarachnoid haemorrhage. Patients enrolled in the randomized. double-blind trial received either placebo or one of 3 doses of tirilazad mesylate (0.6 mglkglday, or 2.0 or 6.0 mglday) for 10 days.

The drug appeared to be well-tolerated and effective in reducing symptomatic vasospasm, cerebral infarction and the use of rescue therapy. It also improved neurological and functional outcome, and reduced death and disability, he said.

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However, a separate study did not show any survival benefit in patients receiving tirilazad mesylate. compared with placebo. Accordingly, the US FDA has postponed its decision regarding approval of the drug, until further efficacy data are available. **

Newer agents in cJinical tria1s Researchers also presented early data from a series

of agents now being tested in clinical trials [see tableJ.

Dextrorphan [Ro-16794J. an NMDA antagonist that is related to the antitussive agent dextromethorphan, has completed phase I studies in patients with acute ischaemic stroke. In these studies, the drug was associated with mild-to-moderate adverse neurological effects. These included nystagmus, somnolence, hallucinations, confusion and hypotension. However, overall tolerability was adequate for researchers to proceed with planning a large. multi centre trial.

i Table: Neuroprotective drugs under developmeDt

I Drug Dextrorphan

Selfotel

Apliganel

Eliprodil

Roc:tle

CIba-Geigy

cambridge Neuroscience

Synth8labo

Phase II

Phase II

Phase II

Phase III

Selfotel [CGS-19755J, another NMDA antagonist. is now in clinical studies in patients with traumatic brain injury and ischaemic stroke . Phase I data in patients with acute ischaemic stroke showed that the drug was generally well tolerated. although a few cases of confusion and agitation were reported.

Eliprodil [SL-820715J has good oral bioavailability. It is currently under investigation in a placebo-controlled trial of 114 patients with acute ischaemic stroke. In pilot studies, the drug had a good clinical safety profile. with no significant clinical or laboratory abnormalities observed.

Meanwhile, back in the laboratory, researchers are beginning to test a number of new therapeutic approaches in animal studies. One promising approach involves neurotrophic factors. such as nerve growth factor. that might encourage nerve cells to regenerate and reconnect. Other approaches being pursued include using the immunosuppressant tacrolimus [FK-506 J, brain cell transplantation, and gene therapy.

* See /npharma 899: 15.7 August 1993; tnJ213003

** See /npharma 959: 22. 22 Oct 1994; 8aJ3fXj285

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