Failure of the competitive N-methyl-D-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two phase III clinical trials. The Selfotel Investigators. Disease-specific amino acid infusion (F080) in hepatic encephalopathy: a prospective, randomized, double-blind, controlled trial. Long-term treatment of latent portosystemic encephalopathy with branched-chain amino acids. A double-blind placebo-controlled crossover study. Quantitative assessment of sustained-release 4-aminopyridine for symptomatic treatment of multiple sclerosis.
Excessive activity of excitatory amino acids released after head trauma has been demonstrated to contribute to progressive injury in animal models and human studies. Several pharmacological agents that act as antagonists to the glutamate receptor have shown promise in limiting this progression. The efficacy of the N-methyl-D-aspartate receptor antagonist Selfotel (CGS 19755) was evaluated in two parallel studies of severely head injured patients, defined as patients with post resuscitation Glasgow Coma Scale scores of 4 to 8.
                A total of 693 patients were prospectively enrolled in two multicenter double-blind studies. Comparison between the treatment groups showed no significant difference with regard to demographic data, previous incidence of hypotension, and severity of injury. As the study progressed, the Safety and Monitoring Committee became concerned about possible increased deaths and serious brain-related adverse events in the treatment arm of the two head injury trials, as well as deaths in the two stroke trials being monitored concurrently. The Selfotel trials were stopped prematurely because of this concern and because an interim efficacy analysis indicated that the likelihood of demonstrating success with the agent if the studies had been completed was almost nil.
                Subsequently, more complete data analysis revealed no statistically significant difference in mortality rates in all cases between the two treatment groups in the head injury trials. In this report the authors examine the studies in detail and discuss the potential application of the data to future trial designs. Seventy-five patients with acute hepatic decompensation superimposed on chronic alcoholic cirrhosis were prospectively randomized for a blinded trial of the treatment of hepatic encephalopathy. The control group received 4 g of enteral neomycin daily along with 25% dextrose by a central venous catheter. The experimental group received a placebo resembling neomycin and isocaloric dextrose plus a modified amino acid mixture enriched with branched-chain amino acids to 36% and deficient in aromatic amino acids and methionine. Thirty patients in the F080 group and 29 in the control group completed the trial. The group receiving the modified amino acid mixture demonstrated a statistically significant improvement in encephalopathy as compared to the neomycin group, while maintaining nitrogen equilibrium. Survival and discharge from the hospital were statistically greater in the group treated with the modified amino acid solution and hypertonic dextrose. Treatment of hepatic encephalopathy in the presence of hepatic decompensation with an amino acid solution formulated for its treatment seems to produce faster, more complete recovery with improved capacity for nutritional support. This trial was undertaken to assess the safety and efficacy of long-term oral supplementation with branched-chain amino acids as an adjunct to conventional therapy in patients with stable cirrhosis and latent encephalopathy. Latent encephalopathy was diagnosed by psychometric testing, used to assess automobile driving capacity. Seventeen patients with impaired driving capacity received either branched-chain amino acids or placebo for 8 weeks before being crossed over to the other regimen for an equal period. Branched-chain amino acids but not placebo significantly improved psychomotor disturbances (p < 0.01) and driving capacity (p < 0.002). No adverse reactions were observed. We conclude that long-term branched-chain amino acid supplementation is well tolerated and effective in the treatment of impaired automobile driving capacity associated with latent portosystemic encephalopathy. To evaluate the efficacy of 4-aminopyridine sustained release (4AP SR) (fampridine, EL-970) using quantitative measures of motor function in multiple sclerosis (MS) patients.
                In vitro, 4AP improves conduction through demyelinated axons. A previous multicenter trial of 4AP SR using the Expanded Disability Status Scale (EDSS) as the primary outcome was unable to establish clinical efficacy.
                Ten MS patients with stable motor deficits (EDSS 6.0-7.5) were given 4AP SR 17.5 mg bid and placebo for 1 week each in a double-blind, placebo-controlled, crossover trial. Time to walk 8 meters, time to climb four stairs, maximum voluntary isometric contraction measured quantitatively (MVICT), manual muscle testing (MMT), grip strength, EDSS, and the patient's global impression were measured.
                Timed gait was improved on 4AP SR compared with placebo in 9 of 10 subjects (p = 0.02). Timed stair climbing, MVICT, MMT, grip strength, and EDSS showed nonsignificant improvements on 4AP SR. Based on their global impressions, seven subjects preferred 4AP SR over placebo; only one preferred placebo. There were no serious side effects.
                4AP SR improved motor function in MS patients. The quantitative outcomes used in this study permit more sensitive evaluation of the therapeutic effect and promise to be useful in future trials of symptomatic treatments for MS.
The case for efficacy of excitatory amino acid inhibitor therapy remains unproven. To date, no product has proven to be efficacious (as determined by the criteria applied) for improving the outcomes of brain-injured patients. Early termination, unpublished, and underpowered studies limit a clear appreciation of the merits of this form of intervention. Additional studies, some of which remain in progress, may more clearly define the efficacy and effectiveness issues.