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. Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial. Controlled trial of intravenous aminophylline in acute cerebral infarction. Prospective, randomized, controlled trial to determine the effect of early enhanced enteral nutrition on clinical outcome in mechanically ventilated patients suffering head injury. [Comparative efficacy of combined therapy with preductal and amino acid composition in elderly patients with coronary heart disease and class II-III angina]. Efficacy of aminophylline in the treatment of acute asthma exacerbation in children.
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. To investigate if ethyl-eicosapentaenoic acid (E-EPA) augmentation improves antipsychotic efficacy and tolerability in first-episode psychosis (FEP).
                We performed a 12-week, randomized, double-blind, placebo-controlled trial of 2-g E-EPA augmentation in 80 FEP patients. Sixty-nine patients were eligible for analysis; a post hoc analysis was computed for a subgroup of nonaffective FEP patients (N = 53). The first participant was included in November 2000 and the last participant completed the trial in August 2003. Primary outcome measures were symptom change scores and time to first response, while tolerability measures and cumulative antipsychotic dose were secondary outcome measures.
                Analysis of covariance controlling for baseline symptoms found no significant mean difference between E-EPA and placebo at week 12 for symptom change scores. Cox regression analysis revealed a significant treatment by diagnosis interaction (p = .024) for time to first response favoring E-EPA in nonaffective psychosis. Post hoc analysis for cumulative response rates further confirmed a higher response rate at week 6 (42.9% [15/35] vs. 17.6% [6/34] for all participants, p = .036; 54.2% [13/24] vs. 17.2% [5/29] for the nonaffective psychosis subset, p = .008); however, the difference at week 12 was no longer significant. Analysis of secondary outcome measures revealed that E-EPA-augmented participants needed 20% less antipsychotic medication between weeks 4 through 6 (p = .03), had less extrapyramidal side effects in the initial 9 weeks (p < .05 for all participants and for all timepoints), and reported less constipation (p = .011) and fewer sexual side effects (p = .016) than those treated with antipsychotic medication alone.
                The findings suggest that E-EPA may accelerate treatment response and improve the tolerability of antipsychotic medications. However, it was not possible to demonstrate a sustained symptomatic benefit of E-EPA in early psychosis, possibly due to a ceiling effect, since a high proportion of first-episode patients already achieve symptomatic remission with antipsychotic medication alone. Further controlled trials in nonaffective early psychosis seem warranted.
                Australian Clinical Trials Registry identifier 12605000267651 (http://actr.org.au). In a double-blind trial intravenous aminophylline was compared with placebo in 79 patients with acute cerebral infarction. Immediate improvement in the neurological evaluation score was significantly more frequent in patients receiving aminophylline (38 per cent) than in those on placebo (15 per cent); only patients with mild or moderately severe strokes responded to the injection. After 3 weeks, however, the treated patients did not fare significantly better than the controls in terms of neurological score and residual disability. Survival rate, length of stay in hospital, and social readaptation were similar in the two groups. It is concluded that intravenous aminophylline in patients with ischaemic strokes can bring about an immediate symptomatic relief, but without appreciably influencing the ultimate recovery. To determine the effect of early enhanced enteral nutrition (EN) on clinical outcome of head-injured patients.
                Prospective, randomized, controlled trial.
                Tertiary neurosurgical and trauma center.
                Eighty-two patients suffering head injury and requiring mechanical ventilation.
                Patients were randomized to receive standard EN (gradually increased from 15 mL/hr up to estimated energy and nitrogen requirements) or enhanced EN (started at a feeding rate that met estimated energy and nitrogen requirements) from day 1. Good neurologic outcome (Glasgow Outcome Scale score of 4 or 5) was determined at 3 and 6 months after injury, and the incidence of infective and total complications was determined during the hospital stay up to 6 months.
                Disease severity assessed by best preintubation Glasgow Coma Scale score, pupillary responses, Injury Severity Score, Acute Physiology and Chronic Health Evaluation II score, computed tomographic scan categorization, and age was similar in both groups. Intervention patients had a higher percentage of energy (p = .0008) and nitrogen (p<.0001) requirements met by EN in the first week after injury. Neurologic outcome at 6 months was similar between groups, but there was a tendency for more intervention patients to have a good neurologic outcome at 3 months than control patients (61% vs. 39%, p = .08). Fewer intervention patients had an infective complication (61% vs. 85%, p = .02) or more than one total complication (37% vs. 61%, p = .046) compared with control patients. Enhanced EN was associated with a reduction in the ratio of serum concentration of C-reactive protein to albumin up to day 6 after injury (p = .004).
                Enhanced EN appears to accelerate neurologic recovery and reduces both the incidence of major complications and postinjury inflammatory responses. A comparative analysis of effectiveness of combined therapy including trimetazidine (preductal) and composition of amino acids (glutamic acid, glycin and cystein) in elderly patients with coronary heart disease and angina of functional class II-III (FC II-III).
                60 patients (47 females and 13 males, mean age 66.4 +/- 0.5 years) with IHD, angina FC II-III, postinfarction cardiosclerosis and circulatory failure stage I-IIA were randomized into 3 randomized groups. Control patients received conventional antianginal therapy with nitrates, beta-adrenoblockers, calcium antagonists, diuretics, ACI inhibitors, cardiac glycosides and aspirin. Patients of group 1 received conventional treatment + complex of amino acids in dose 100 mg 3 times a day sublingually. Group 2 patients received adjuvant preductal for 20 days in dose 20 mg 3 times a day per os. Assessment was made clinically, with echo-CG data, bimanual isometric loading and Holter 24-h ECG monitoring.
                All the three methods showed antianginal, hypotensive effects, brought higher tolerance to exercise and improvement of hemodynamics. The basic therapy produced the least effect.
                Metabolic therapy with amino acids and preductal combined with conventional methods brings more pronounced antianginal and hemodynamic effects than combined therapy alone. The role of aminophylline (ethylene diamine salt of theophylline) in the treatment of acute exacerbation of asthma has not been well established in children.
                The aim of the study was to determine the additional therapeutic benefit of intravenous aminophylline in the treatment of children hospitalized for acute asthmatic exacerbation and treated with inhaled bronchodilators and glucocorticoid therapy.
                Thirty-eight children aged from 2 to 16 years (mean age 5.64 +/- 3.31), admitted for acute exacerbation of asthma, participated in a prospective, randomized, double-blind, placebo-controlled study. All the subjects received methylprednisolone, administered intravenously, and nebulized salbutamol. The treatment group received intravenous aminophylline therapy and the placebo group received 0.9% saline solution for 24 hours.
                The number of salbutamol nebulizations needed and the clinical asthma scoring were recorded both at onset and at the end of 24 hours. There was no significant difference in either the mean number of nebulizations or the clinical asthma scores between the two groups (P = .7843, P = .8452).
                Intravenous aminophylline (ethylene diamine salt of theophylline) demonstrated no additional beneficial effect to the combination of beta adrenergic agonists and glucocorticoid treatment in acute asthma attack in children.
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.