Piracetam Is Neuroprotective

Large-scale study shows good outcome with early treatment among acute stroke patients

Cerebrovascular disease is now the leading cause of morbidity and mortality worldwide. It is also the most common cause of chronic disability.

    Stroke is preventable, but when it happens, management shifts to limiting damage and its long-term debilitating effects, preventing chronic disability, and speeding up recovery. Thus, treatment should focus not only on the local immediate effects but also on the recovery phase.

    In addressing acute ischemic stroke, Dr. Peter Paul De Deyn, head of laboratory neurochemistry and behavior at the University of Antwerp and the Neurology Department at the General Hospital of Middleheim, pointed to two approaches. "One is the restoration of cerebral blood flow and the other is neuroprotection--protecting the ischemic neurons from cell death," he told Filipino physicians during a symposium organized by UCB Philippines, Inc.

    Focusing on pharmacological intervention, Dr. De Deyn reviewed studies involving various classes of drugs used in either of the two management approaches.

Blood Flow Restoration

    There are at least six classes of drugs used for blood flow restoration. These are the thrombolytics, the anticoagulants, the antiplatelets, the vasodilators, drugs with effects on microcirculation, and the hemorrheological drugs.

    Dr. De Deyn noted that results of studies on these drugs have not been impressive.

    He observed that clinical trials on thrombolytics used intra-arterially have been largely limited in number with the results "somewhat contradictory." On the other hand, studies on intravenous thrombolytics, particularly the MAST-1, MAST-E, and Australian Streptokinase study, yielded results characterized by side effects and increased mortality rate. They had to be prematurely terminated because of safety issues.

    A ray of light was observed in the National Institute of Neurological Disorders Stroke trial on recombinant tissue plasminogen activator (rTPA), wherein early administration of rTPA (within three hours after stroke) produced better neurologic and functional outcome. But Dr. De Deyn said that when the time window for treatment was increased from three to six hours, safety and efficacy became a problem.

    The story of anticoagulants is a "tricky" one, according to Dr. De Deyn. The International Stroke Trial (IST) showed heparin has no effects, only side effects. On the other hand, a 1995 paper by Kay et al. indicated that fraxiparine administered at 4,200 and 8,200 IU "showed a tendency towards improvement of mortality and independency outcomes after six months of initial treatment. "But the study showed only statistical trends, observed Dr. De Deyn, prompting initiation of new clinical trials, particularly those involving low molecular weight heparin.

    As for antiplatelet drugs, Dr. De Deyn said studies have shown that aspirin has no effect on the primary stroke outcome although it has a positive impact on secondary prevention. Meanwhile studies on vasodilating agents yielded inconclusive results while that involving enlimomab was terminated early due to safety issues.

Neuroprotection

    Neuroprotectant drugs include calcium channel-blockers, inhibitors of excitatory amino acids such as glycine and glutamate antagonists, membrane stabilizers like nootropics, free-radical scavengers, and the nitric oxide donors.

    Studies on the neuroprotectants had better results. This is typified by piracetam (Nootropil), a cerebrovascular enhancer or nootropic agent that has been widely used for the treatment of impaired cerebral function in aging, and in a number of disabilities such as vertigo and central nervous system (CNS) damage. Piracetam has a protective and restorative effect on the neuronal membrane and neurotransmission. It also has hemorrheological properties such as increasing the deformability of red blood cells, and antiplatelet/antithrombotic effects.

    Previous studies on piracetam by Herrschaft et al. and Platt et al. have shown significant and beneficial effects on paresis, consciousness, aphasia, sensory problems and on SPECT scans. "And these were the reasons why we set out to perform the Piracetam in Acute Stroke Study (PASS), which was published in the journal Stroke," Dr. De Deyn beamed. He noted that because of piracetam's neuroprotective, antithrombotic, membrane-stabilizing effects, "which are obtained by direct physico-chemical interaction with cell and mitochondrial membranes, it is important to stress that piracetam is active not only on neurons but also on the membranes of other cells. It has polyvalent features and mechanisms of activity."

    The PASS study included patients with acute (<12hrs) onset of stroke, with symptoms indicating an acute hemispheric stroke, with Orgogozo ratings from five to 70 and with initial CT scans showing a supratentorial infarct of >1cm3. Medications such as aspirin, standard and low molecular weight heparins, vitamin K antagonists, and calcium channel antagonists were allowed. Piracetam was administered intravenously for four days, then either maintained on IV administration or shifted to oral (syrup) formulation for another four weeks, and then maintained on an oral (pill) administration for eight weeks.

    Treatment efficacy was assessed based on the post-treatment neurological (Orgogozo scores) and functional (Barthel) outcomes. Improvements in aphasia were also assessed using the Frenchay Aphasia Screening test. The results were significant within these parameters. Compared with placebo, there were significant improvements in the Orgogozo and Barthel scales, especially in the subpopulation of patients who were treated in the early (< 6h) phase (Figures 1 and 2).

    Said Dr. De Deyn: "The difference is not only statistically significant, but also clinically significant. Now you have individuals who function better." Even in patients with moderate to severe deficit (Orgogozo score <55) there were significant improvements after piracetam treatment. "It shows that the beneficial effects of piracetam are not only present in the acute phase but also in the later phase, because you see that the improvement continues to be present after 12 weeks of treatment," Dr. De Deyn noted. Approximately 25 percent of piracetam recipients reached a higher class of independency (Barthel index = 100).

    As regards aphasia, again in the early (<6hrs) treatment group, there was a significant increase in patients recovering from aphasia after 84 days of treatment (37 percent vs 21 percent; p = 0.02 vs placebo). "What we see here is that 16 percent more patients recuperate from their stroke when treated with piracetam within seven hours of stroke onset," Dr. De Deyn said.

    The overall safety of piracetam was also assessed, with the number of side effects almost comparable with that of placebo. But Dr. De Deyn enumerated some interesting observations that merited some attention. "One is convulsion, where there were only seven cases in the piracetam group compared to 13 in the placebo group. This indicates that piracetam has some anti-epileptic effect."

    The incidence of psychiatric symptoms was also lower among the piracetam recipients than those given placebo (50 vs 57), "in contrast with other neuroprotective agents such as the receptor antagonists."

    Dr. De Deyn said piracetam has consistently proved to be very beneficial for aphasia and with good neurological and functional outcome among patients treated within 12 hours of stroke onset. PASS has been the first large-scale study to show that it is possible to improve outcome among acute ischemic stroke patients with early treatment using an agent that both protects the neurons and improves perfusion.