A single dose, three-arm, placebo-controlled, phase I study of the bradykinin B2 receptor antagonist Anatibant (LF16-0687Ms) in patients with severe traumatic brain injury. Effects of the bradykinin antagonist Bradycor (deltibant, CP-1027) in severe traumatic brain injury: results of a multi-center, randomized, placebo-controlled trial. American Brain Injury Consortium Study Group. The BRAIN TRIAL: a randomised, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant) in patients with traumatic brain injury. A double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of CP-101,606 in patients with a mild or moderate traumatic brain injury. Traumatic brain contusions: a clinical role for the kinin antagonist CP-0127. Low dose beta blockade in acute stroke ("BEST" trial): an evaluation. 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. The treatment of agitation during initial hospitalization after traumatic brain injury. Selectivity of beta adrenoreceptor antagonist drugs assessed by histamine bronchial provocation.
Traumatic brain injury (TBI) mortality and morbidity remains a public health challenge. Because experimental studies support an important role of bradykinin (BK) in the neurological deterioration that follows TBI, a double-blind, randomized, placebo-controlled study of Anatibant (LF16- 0687Ms), a selective and potent antagonist of the BK B(2) receptor, was conducted in severe (Glasgow Coma Scale [GCS] < 8) TBI patients (n = 25) at six sites in the United States. At 8-12 h after injury (9.9 +/- 2.8 h), patients received a single subcutaneous injection of Anatibant (3.75 mg or 22.5 mg, n = 10 each) or placebo (n = 5). The primary objective was to investigate the pharmacokinetics of Anatibant; general safety, local tolerability, levels of the bradykinin metabolite BK1-5 in plasma and cerebrospinal fluid (CSF), intracranial pressure (ICP), and cerebral perfusion pressure were also assessed. We observed a dose-proportionality of the pharmacokinetics, Cmax, and AUC of Anatibant. V(d)/F, Cl/F, and t(1/2) were independent on the dose and protein binding was >97.7%. Anatibant, administered as single subcutaneous injections of 3.75 g and 22.5 mg, was well tolerated in severe TBI patients with no unexpected clinical adverse events or biological abnormalities observed. Interestingly, plasma and CSF levels of BK1-5 were significantly and markedly increased after trauma (e.g., 34,700 +/- 35,300 fmol/mL in plasma vs. 34.9 +/- 5.6 fmol/mL previously reported for normal volunteers), supporting the use of Anatibant as a treatment of secondary brain damage. To address this issue, a dose-response trial that would investigate the effects of Anatibant on the incidence of raised ICP and on functional outcome in severe TBI patients is needed. A phase II prospective, randomized, double blind clinical trial of Bradycor, a bradykinin antagonist, was conducted at 31 centers within North America in severely brain injured patients. Patients of Glasgow Coma Score (GCS) 3-8 (n = 139) with at least one reactive pupil were randomized to receive either Bradycor, 3 microg/kg/min or placebo as a continuous intravenous infusion for 5 days, with the infusion beginning within 12 h of the injury. The primary objective was to assess the efficacy of a continuous infusion of Bradycor (3.0 mc/kg/min) in preventing elevation of intracranial pressure (ICP). Other efficacy measures included the effect of Bradycor on the Therapy Intensity Level (TIL), mortality, and functional outcome. A secondary objective was to evaluate the safety of Bradycor in patients with severe brain injury. Randomization was carried out according to a computer generated randomization list. Patients were followed for the first 14 days of hospitalization with long-term outcome assessed at 3 and 6 months after injury. During the infusion and while the ICP monitor was in place, ICP measurements were recorded hourly along with blood pressure and heart rate. A modified version of the TIL was used to record therapeutic interventions hourly, while the ICP was being monitored. Outcome was assessed at 3 and 6 months after injury using the Glasgow Outcome Score (GOS). Bradycor was well tolerated in this patient population, and no adverse events were attributable to the compound. Although positive trends were seen for both ICP and TIL in the Bradycor group, these differences analyzed on a daily basis were not significant. However, a mixed model of variance which included treatment, day, treatment by day interaction, age and GCS revealed that the percentage time ICP of >15 mm Hg on days 4 and 5 was significantly lower in the Bradycor group compared to placebo (p = 0.035). There were fewer deaths in the Bradycor group, which had a 28-day all cause mortality of 20% versus 27% on placebo. Patients treated with Bradycor showed a 10.3% improvement in favorable outcome at 3 months and a 12% improvement in dichotomized GOS at 6 months (p = 0.26). The consistent positive trends seen in ICP, TIL, neuropsychological tests, and, most importantly, 3- and 6-month GOS provide supportive evidence that a bradykinin antagonist may play a neuroprotective role in severe brain injury. Cerebral oedema is associated with significant neurological damage in patients with traumatic brain injury. Bradykinin is an inflammatory mediator that may contribute to cerebral oedema by increasing the permeability of the blood-brain barrier. We evaluated the safety and effectiveness of the non-peptide bradykinin B2 receptor antagonist Anatibant in the treatment of patients with traumatic brain injury. During the course of the trial, funding was withdrawn by the sponsor.
                Adults with traumatic brain injury and a Glasgow Coma Scale score of 12 or less, who had a CT scan showing an intracranial abnormality consistent with trauma, and were within eight hours of their injury were randomly allocated to low, medium or high dose Anatibant or to placebo. Outcomes were Serious Adverse Events (SAE), mortality 15 days following injury and in-hospital morbidity assessed by the Glasgow Coma Scale (GCS), the Disability Rating Scale (DRS) and a modified version of the Oxford Handicap Scale (HIREOS).
                228 patients out of a planned sample size of 400 patients were randomised. The risk of experiencing one or more SAEs was 26.4% (43/163) in the combined Anatibant treated group, compared to 19.3% (11/57) in the placebo group (relative risk = 1.37; 95% CI 0.76 to 2.46). All cause mortality in the Anatibant treated group was 19% and in the placebo group 15.8% (relative risk 1.20, 95% CI 0.61 to 2.36). The mean GCS at discharge was 12.48 in the Anatibant treated group and 13.0 in the placebo group. Mean DRS was 11.18 Anatibant versus 9.73 placebo, and mean HIREOS was 3.94 Anatibant versus 3.54 placebo. The differences between the mean levels for GCS, DRS and HIREOS in the Anatibant and placebo groups, when adjusted for baseline GCS, showed a non-significant trend for worse outcomes in all three measures.
                This trial did not reach the planned sample size of 400 patients and consequently, the study power to detect an increase in the risk of serious adverse events was reduced. This trial provides no reliable evidence of benefit or harm and a larger trial would be needed to establish safety and effectiveness.
                This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN23625128. CP-101,606 is a postsynaptic antagonist of the glutamate-mediated NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor. When administered intravenously (i.v.) at the time of injury, CP-101,606 is neuroprotective in animal models of traumatic brain injury (TBI) and ischemia. Minimal adverse effects have been observed in normal human volunteers given i.v. doses of up to 3 mg/kg/hr for 72 hours. The objective of the present clinical trial was to assess the safety, pharmacokinetics, and tolerability of CP-101,606 infused for various times in patients who had suffered either an acute moderate or mild TBI (Glasgow Coma Score 9-14) or hemorrhagic stroke. Patients began receiving treatment within 12 hours of brain injury. A total of 53 subjects (45 with TBI and 8 with stroke) were randomized in a double-blind fashion to receive CP-101,606 or placebo (4 drug: 1 placebo). Drug/placebo was administered by i.v. infusion (0.75 mg/kg/hr) for 2 hours and then stopped (n = 25) or continued for 22 hours (n = 4) or 70 hours (n = 24) at a rate of 0.37 mg/kg/hr. Mean plasma drug concentrations were well above the predicted therapeutic concentration of 200 ng/ml within two hours of initiating treatment and were sustained as long as drug was infused. All the patients tolerated their drug/placebo treatment, and there were no clinically significant cardiovascular or hematological abnormalities in either group. A Neurobehavioral Rating Scale, used to detect personality changes and behavioral disturbances, indicated that all subjects showed an improvement from their postinjury, predosing baseline but did not significantly differ from each other with respect to type of head injury and/or treatment with drug or placebo. Modified Kurtzke Scoring also showed a similar pattern of improvement irrespective of type of head injury or drug/placebo treatment. This study suggests that CP-101,606, infused for up to 72 hours has no psychotropic effects and is well-tolerated in patients who have sustained a mild or moderate TBI or hemorrhagic stroke. Focal cerebral contusions can be dynamic and expansive, leading to delayed neurological deterioration. Due to the high mortality associated with such cerebral contusions, our standard practice had evolved into evacuating contusions in patients who had a deterioration in level of consciousness, lesions > 30 cc and CT suggestion of raised ICP. Experimental brain edema studies have implicated kinins in causing 2 degrees brain swelling. CP-0127 (Bradycor), a specific bradykinin antagonist, has been found to reduce cerebral edema in a cold lesion model in rats. In a randomized, single blind pilot study, a 7 day infusion of CP-0127 (3.0 micrograms/kg/min) was compared to placebo in patients with focal cerebral contusions presenting within 24-96 hours of closed head injury with an initial GCS 9-14. The ICP, GCS, and vital signs were monitored hourly. The total lesion burden (TLB) was measured on serial CT scans. There were no differences in age, baseline GCS, TLB, initial ICP, or laboratory findings between the two groups (n = 20). The mean (+/- s.d.) rise in peak ICP from baseline was greater in the placebo group than with CP-0127 (21.9 +/- 4.7 vs 9.5 +/- 2.0, P = 0.018). In addition, the mean reduction in GCS in the placebo group was significantly greater than in the CP-0127 group (4 +/- 1.0 vs 0.6 +/- 0.4, P = 0.002). Significantly raised ICP and clinically significant neurological deterioration occurred in 7/9 patients on placebo (77%) and only in 1 patient (9%; n = 11) on CP-0127, mandating surgery (P = 0.005). There were no adverse drug reactions, significant changes in vital signs or variations in the laboratory values. The cerebral perfusion pressure was adequately maintained in all patients irrespective of therapy. These preliminary results with CP-0127 provide supporting evidence that the kinin-kallikrein system could be involved in cerebral edema. In this study, treatment with CP-0127 appeared to alter the natural history of traumatic brain contusions by preventing the 2 degrees brain swelling. In addition, CP-0127 obviated the need for surgery in the majority of treated patients. CP-0127 could act on the cerebral vasculature to limit dys-autoregulation and brain swelling or on the blood brain barrier to reduce cerebral edema. The beta blocker stroke ("BEST") trial was designed to see if the apparent protective effect of propranolol on cerebral function in patients with subarachnoid haemorrhage applied also to patients suffering from acute stroke. Three hundred and two conscious patients with clinically diagnosed hemispheric strokes sustained within the past 48 hours were randomly assigned to receive atenolol, propranolol, or matching placebo capsules for three weeks. More early deaths occurred among the patients allocated to receive beta blockers, but this was largely explained by differences in the initial characteristics of the patients among the different treatment groups. By contrast, the outcome in a further 60 patients, who had been taking beta blockers at the time of their stroke but were otherwise similar to the patients in the trial, was considerably better, suggesting that prior treatment with beta blockers might be protective. The search for an effective medical treatment for acute stroke must continue. The approach used here, in which neurological outcome was assessed in a modest number of patients with a view to proceeding subsequently to a full scale trial of functional outcome, allows practical benefits of a treatment to be evaluated under realistic conditions and an ineffective treatment to be eliminated without undue cost. 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. Agitation after traumatic brain injury is disruptive for patient care, distressing, and difficult to treat. The use of propranolol has been advocated to control agitation after brain injury. It reportedly lacks some of the deleterious cognitive and emotional effects of other medications and physical restraints. This study was designed to test if propranolol is effective in reducing agitated behavior. Subjects had traumatic closed-head injury treated at a combined Level I Trauma Center and Rehabilitation Center. Twenty-one subjects met the criteria of agitation and were treated with propranolol or placebo in a double-blind fashion. The intensity of agitation was significantly lower in the treatment group although the number of episodes were similar. The use of restraints was also significantly lower in the treatment group. The results support the effectiveness of propranolol in reducing the intensity of agitation during the initial hospitalization after closed-head injury. In a double-blind, within-patient, randomized study, 12 mild asthmatics were given single oral doses of propranolol (80 mg), metoprolol (100 mg), timolol (10 mg), or placebo. Resting heart rate and forced expiratory volume in one sec (FEV1) were measured before and 90 min after treatment. Nonspecific bronchial reactivity was measured by inhaled histamine at 90 min. Following each active drug, resting heart rate changed to a similar extent and to a greater degree than after placebo (p less than 0.01). Changes in FEV1 were small and not different from those after placebo. In contrast, after each active drug, bronchial reactivity increased more than after placebo. The degree of reactivity with each active drug was similar but the differences from corresponding placebo values were significant (p less than 0.05). We conclude that, in mild asthmatics, nonspecific bronchial reactivity is a more sensitive index of airway effects than resting FEV1. Moreover, in the context of this study, since the beta-blockers were given in doses likely to induce equivalent cardiac beta-blockade, there is no evidence to suggest that any one of them is more "cardioselective" than the others.
There is no reliable evidence that bradykinin beta-2 receptor antagonists are safe or effective for use in TBI patients, and they should not be used outside the context of well conducted trials. Further adequately powered and well conducted randomised controlled trials are required.