deltibant and Brain-Injuries

Early pharmacological treatment has the potential to reduce some of the disabling cognitive and behavioral problems that result from traumatic brain injury (TBI). Although a large number of treatments have been developed, clinical research has yielded inconsistent findings with respect to the effectiveness of these pharmacological treatments on cognitive and behavioral outcomes. Furthermore, their relative efficacy has not been evaluated, thereby hindering advances in the treatment of TBI. A meta-analysis of research that examined the impact of pharmacological treatments on cognitive and behavioral outcomes in the early stages after TBI between January 1980 and May 2008 was therefore undertaken. The PubMed and PsycINFO databases were searched using 35 terms. All articles were screened using detailed inclusion criteria. Weighted Cohen's d effect sizes, percent overlap statistics, and fail-safe N statistics were calculated for each pharmacological agent. Studies that used different experimental designs were examined separately. Eleven pharmacological treatments were investigated by 22 clinical studies, comprising 6472 TBI patients in the treatment groups and 6460 TBI controls. One dopamine agonist (amantadine) and 1 bradykinin antagonist (CP-0127 [Bradycor]) produced marked treatment benefits (d > or = 0.8) for a single measure of arousal (Glasgow Coma Scale). Notably, drug dosage and the measure chosen to assess outcome influenced the probability of finding a treatment benefit.

Topics: Adult; Amantadine; Behavior; Brain Injuries; Cognition Disorders; Controlled Clinical Trials as Topic; Female; Humans; Male; Neuropsychological Tests; Peptides; Time Factors; Treatment Outcome

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Cerebral oedema, the accumulation of fluid within the brain, is believed to be an important contributor to the secondary brain damage that occurs following injury. The release of kinins is thought to be an important factor in the development of cerebral vasogenic oedema and the use of beta-2 receptor antagonists, which prevent the release of these kinins, have been proposed as a potential therapeutic intervention.. The objective was to assess the safety and effectiveness of beta-2 receptor antagonists for TBI.. We searched the Cochrane Injuries Group's specialised register, CENTRAL, MEDLINE, EMBASE, National Research Register, LILACs, Zetoc, Web of Knowledge and Current Controlled Trials. We also searched the internet and checked the reference lists of relevant papers to identify any further studies. The searches were conducted in March 2007.. Randomised controlled trials of beta-2 receptor antagonists versus placebo for TBI.. Two authors independently screened search results and assessed the full texts of potentially relevant studies for inclusion. Data were extracted and methodological quality was examined. Relative risks (RR) and 95% confidence intervals (CIs) were calculated and data were pooled using a fixed effect model.. Three studies were included, involving 178 participants. All three studies reported the effects of beta-2 receptor antagonists on mortality. The pooled RR for mortality was 0.63 (95% CI 0.36 to 1.10). Two studies measured disability, the RR of death or severe disability with beta-2 receptor antagonists was 0.81 (95% CI 0.59 to 1.09). Two studies measured the effect on intracranial pressure (ICP), although in only one did this finding reach statistical significance. There was no evidence for the presence of heterogeneity.. There is no reliable evidence that beta-2 receptor antagonists are effective in reducing mortality or disability after TBI. Further well conducted randomised controlled trials are required.

Topics: Acute Disease; Adrenergic beta-2 Receptor Antagonists; Brain Edema; Brain Injuries; Humans; Intracranial Pressure; Peptides; Quinolines; Randomized Controlled Trials as Topic

Bradykinin, an endogenous nonapeptide produced by activation of the kallikrein-kinin system, promotes neuronal tissue damage as well as disturbances in blood-brain barrier function, mainly through the activation of B2 receptors. Both cerebral ischemia and trauma are associated with an activation of the kallikrein-kinin system, resulting in a sustained production of kinins. This is strong evidence supporting an involvement of bradykinin-mediated secondary brain damage following cerebral ischemia and trauma. Accordingly, specific inhibition of bradykinin B2 receptors attenuates brain swelling and limits tissue damage, indicating its potential in patients with acute cerebral ischemia and trauma.

Topics: Animals; Bradykinin Receptor Antagonists; Brain Injuries; Brain Ischemia; Drugs, Investigational; Humans; Peptides; Receptors, Bradykinin

These data and others indicate that the kallikrein/kinin system is activated in both systemic and central nervous system trauma and that specific kinin antagonists are active in animal models of systemic and CNS trauma. In addition, preliminary data in humans suggest that kinin antagonists may have a role in the management of traumatic brain injury. Clearly, further studies in these indications are indicated.

Topics: Animals; Blood-Brain Barrier; Bradykinin Receptor Antagonists; Brain Injuries; Humans; Kallikrein-Kinin System; Kinins; Peptides; Peroxidase; Receptor, Bradykinin B2; Respiratory Distress Syndrome; Wounds and Injuries

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.

Topics: Adolescent; Adult; Aged; Bradykinin Receptor Antagonists; Brain Injuries; Double-Blind Method; Female; Glasgow Coma Scale; Humans; Intracranial Pressure; Male; Middle Aged; Neuroprotective Agents; Neuropsychological Tests; Peptides; Prospective Studies; Quality of Life; Time Factors; Treatment Outcome