Deltibant

The kallikrein-kinin system plays an important role in many physiological and pathophysiological conditions such as homeostasis of circulation, inflammation/allergy, pain, shock, etc. Two types of kinin receptor are known, bradykinin (BK) B1 receptor and BK B2 receptor. B2 receptors are constitutively expressed and mediate most physiological actions of kinins, whereas B1 receptors are highly inducible upon inflammatory stimulation or tissue injury, suggesting that they are involved in inflammation and/or nociception. Only three peptide type B2 antagonists, NPC 567, CP-0127 and HOE-140, have been evaluated in clinical studies so far, and some beneficial effects of B2 antagonists have been shown for rhinitis, asthma, systemic inflammatory response syndrome/sepsis and brain injury. However, the results were less convincing than expected. Now several potent and orally active nonpeptide B2-receptor antagonists have been found, which are expected to overcome the weak point of the peptide type antagonists and clarify the therapeutic potential of the B2-receptor antagonist for novel indications as well as those mentioned above. As for B1 receptors, no antagonist has been tested in a clinical trial. The important role of B1 receptors is just being elucidated by use of peptide type antagonists or B1 receptor gene knockout mice. The further development of newer B1 antagonists and clinical evaluation is desired.

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.