anatibant and Brain-Injuries

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

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.

Topics: Adult; Bradykinin B2 Receptor Antagonists; Brain Injuries; Glasgow Coma Scale; Humans; Inflammation Mediators; Morbidity; Placebo Effect; Quinolines; Risk Factors

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.

Topics: Adolescent; Adult; Aged; Area Under Curve; Bradykinin; Bradykinin B2 Receptor Antagonists; Brain Injuries; Double-Blind Method; Female; Glasgow Outcome Scale; Half-Life; Humans; Male; Middle Aged; Peptide Fragments; Pilot Projects; Quinolines

Bradykinin, the main metabolite of the kallikrein-kinin system and one of the first mediators released during inflammation, is well known to increase the permeability of the blood brain barrier (BBB) by activation of kinin B2 receptors and hence promote brain edema formation following traumatic brain injury (TBI). Anatibant (LF 16-0687), a selective non-peptide bradykinin B2 receptor antagonist, reduces brain edema after experimental TBI, however, so far no data are available if Anatibant reduces also the sequels of brain edema formation, i.e. morphological brain damage. Therefore, we investigated the effect of Anatibant (3.0 mg/kg b.w.) on intracranial pressure (ICP) and contusion volume after experimental TBI. Male C57/Bl6 mice (25-28 g) were subjected to Controlled Cortical Impact trauma (CCI). Anatibant was administrated as a subcutaneous bolus 15 min and 8h after TBI. ICP was measured 3, 6, and 10 h after injury and contusion volume was quantified 24 h after trauma. Our data demonstrate a significant reduction of ICP (16.6+/-1.67 mmHg vs. 24.40+/-3.58 mmHg; n=6; p=0.002) and of contusion volume 24 h after trauma (28.28+/-5.18 mm3 vs. 35.0+/-3.32 mm3 n=7; p=0.003) in treated mice. Therefore we conclude, that inhibition of bradykinin B2 receptors seems to be a promising treatment option, and might therefore be investigated in clinical trails for the treatment of TBI.

Topics: Animals; Bradykinin B2 Receptor Antagonists; Brain; Brain Injuries; Injections, Subcutaneous; Intracranial Hypertension; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Quinolines

A response to and comment on The BRAIN TRIAL: a randomised, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant) in patients with traumatic brain injury, by Haleema Shakur, Ian Roberts, et al.

Topics: Bradykinin B2 Receptor Antagonists; Brain Injuries; Humans; Placebos; Quinolines; Randomized Controlled Trials as Topic

Inhibition of the bradykinin B2 receptor type (B2R) has been shown to improve neurological outcome in models of focal traumatic brain injury. However, the involvement of B2R in trauma-induced diffuse injury has not yet been explored. This is an important point, since in humans a pattern of diffuse injury is commonly found in severely injured patients and has been associated with a poor neurological outcome and prognosis. Using the non-peptide B2R antagonist LF 16-0687 Ms and B2R null (B2R-/-) mice, we investigated the role of B2R in a model of closed head trauma (CHT). LF 16-0687 Ms given 30 min after injury reduced the neurological deficit by 26% and the cerebral edema by 22% when evaluated 4 h after CHT. Neurological function after CHT was improved in B2R-/- mice compared to B2R+/+ mice, although there was no difference in the development of brain edema. Treatment with LF 16-0687 Ms and B(2)R gene deletion decreased the accumulation of neutrophils at 24 h after CHT (50% and 36%, respectively). In addition, the inducible NO synthase (iNOS) mRNA level increased markedly, and this was reduced by LF 16-0687 Ms. Taken together, these data support a detrimental role of B2R in the development of the neurological deficit and of the inflammatory secondary damage resulting from diffuse traumatic brain injury. Therefore, blockade of bradykinin B2 receptors might represent an attractive therapeutic approach in the pharmacological treatment of traumatic brain injury.

Topics: Animals; Bradykinin B2 Receptor Antagonists; Brain Injuries; Disease Models, Animal; Gene Deletion; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Quinolines; Receptor, Bradykinin B2

Bradykinin is an endogenous inflammatory agent that enhances vascular permeability and produces tissue edema. We investigated whether LF 16-0687 Ms, a potent nonpeptide antagonist of bradykinin type-2 (B(2)) receptor, was able to reduce brain swelling and to improve the recovery of neurological function following closed head trauma (CHT) in rats. In dose-effect studies, LF 16-0687 Ms doses of 0.75-4.5 mg/kg given 1 h after trauma significantly reduced the development of edema in the injured hemisphere by a maximum of 70%. It had no effect on the brain water content of sham-operated rats. LF 16-0687 Ms also significantly improved neurological recovery evaluated by a Neurological Severity Score (NSS) based on motor, reflex, and behavioral tests. In time-window studies LF 16-0687 Ms (2.25 mg/kg) was given 1, 2, 4, and 10 h after CHT. The extent of edema was significantly reduced when LF 16-0687 Ms was given 1 h (-45%), 2 h (-52%), and 4 h (-63%) but not 10 h (-24%) after CHT. Given at any time-point, LF 16-0687 Ms significantly improved the recovery of the NSS at 24 h. In duration of treatment studies, rats tended to recover normal neurological function over 14 days after CHT. However, time to recovery was longer in severely than in moderately injured animals, unless they were treated with LF 16-0687 Ms. This study provides further evidence that blockade of bradykinin B(2) receptors represents a potential effective approach to the treatment of focal cerebral contusions.

Topics: Animals; Bradykinin Receptor Antagonists; Brain Edema; Brain Injuries; Dose-Response Relationship, Drug; Head Injuries, Closed; Neuroprotective Agents; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Recovery of Function; Time Factors; Trauma Severity Indices

Identification of new therapeutic agents aimed at attenuating posttraumatic brain edema formation remains an unresolved challenge. Among others, activation of bradykinin B2 receptors is known to mediate the formation of brain edema. The purpose of this study was to investigate the protective effect of the novel nonpeptide B2 receptor antagonist, LF 16-0687Ms, in brain-injured rats.. Focal contusion was produced by controlled cortical impact injury. Five minutes after trauma, the rats received a single dose of no, low- (3 mg/kg body weight), or high- (30 mg/kg) dose LF 16-0687Ms. After 24 hours, the amount of brain swelling and hemispheric water content were determined. Low and high doses of LF 16-0687Ms significantly reduced brain swelling by 25% and 27%, respectively (p < 0.03). Hemispheric water content tended to be increased in the nontraumatized hemisphere. In a subsequent series of 10 rats, cisternal cerebrospinal fluid (CSF) samples were collected to determine whether changes in substances associated with edema formation could clarify why LF 16-0687Ms increases water content. For this, the volume regulator amino acid taurine, the excitatory transmitter glutamate, and the adenosine triphosphate degradation products hypoxanthine and xanthine were measured. In CSF, the levels of taurine, hypoxanthine, and xanthine were significantly decreased following a single administration of LF 16-0687Ms (p < 0.005); the level of glutamate, however, was double that found in control animals (p < 0.05).. Using the present study design, a single administration of LF 16-0687Ms successfully reduced posttraumatic brain swelling. The decreased levels of taurine, hypoxanthine, and xanthine may reflect reduced posttraumatic brain edema, whereas the increased level of glutamate could account for the elevated water content observed in the nontraumatized hemisphere.

Topics: Analysis of Variance; Animals; Body Water; Bradykinin Receptor Antagonists; Brain Chemistry; Brain Edema; Brain Injuries; Glutamic Acid; Hypoxanthine; Injections, Subcutaneous; Kinins; Male; Neuroprotective Agents; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Taurine; Xanthine