deltibant and icatibant

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.

Topics: Asthma; Bradykinin; Bradykinin Receptor Antagonists; Humans; Hypersensitivity; Peptides; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Rhinitis; Systemic Inflammatory Response Syndrome

In search of new possibilities to prevent acute inflammatory vascular reaction, we examined the effect of two selective B2 receptor antagonists, CP 0127 ([Bissuccimidohexane (L-Cys6)-1] and HOE 140 (D-Arg[Hyp3, Thi5, D-Tic7, Oic8]BK), on changes in perfusion pressure and on edema formation caused by bradykinin (BK) in the isolated perfused rabbit hindlimbs. CP 0127 and HOE 140 were added to the perfusion fluid 2 min prior to the first BK-administration (5 x 10(-9) mol/l). A second BK-stimulation was performed after 30 minutes. The antagonists were tested in groups of 6 experiments each at concentrations of 10(-6) mol/l, 5 x 10(-9) mol/l and 10(-10) mol/l. CP 0127 was also tested in a concentration of 10(-8) mol/l. The application of BK resulted in an acute decrease of the mean arterial pressure and in a continual edema formation, reflected by an increase of organ weight (controls, n = 6). Pretreatment with CP 0127 as well as with HOE 140 attenuated dose-dependently the BK-induced vasodilation (p < 0.005) and edema formation. The current results indicate that CP 0127 and HOE 140 are able to reduce BK-induced effects on vascular tone and edema formation.

Topics: Amino Acid Sequence; Animals; Bradykinin; Bradykinin Receptor Antagonists; Edema; Female; Hindlimb; Male; Molecular Sequence Data; Peptides; Rabbits; Receptors, Bradykinin; Vasodilation

Topics: Amino Acid Sequence; Animals; Bradykinin; Humans; Kinins; Molecular Sequence Data; Oligopeptides; Peptides; Shock, Septic