Bradykinin B2 antagonist - icatibant
Bradykinin is an endogenous nonapeptide that has both positive and negative effects in the body. There are two G-coupled receptor subtypes, B1 and B2, and in vitro studies indicate that the physiological effects caused by activity at the B2 receptors are rapidly reversible.
Bradykinin is an endogenous nonapeptide that has both positive and negative effects in the body. There are two G-coupled receptor subtypes, B1 and B2, and in vitro studies indicate that the physiological effects caused by activity at the B2 receptors are rapidly reversible.
Bradykinin has potent proinflammatory effects, including causing hypotension, inflammatory pain and vasodilation, and the B2 receptor is believed to be involved in most of these. As a result, blocking the receptor might be expected to have antiallergic, anti-inflammatory and antihyperalgesic effects, and thus a B2 antagonist might have a number of potential therapeutic uses.
The B2 antagonist icatibant is being looked at by German company Jerini, and also the originating company Sanofi-Aventis, as a potential treatment in several indications.1 These include cirrhosis, asthma, hereditary angio-oedema, oedema from burns and osteoarthritis.
The drug has been investigated as a nebulised treatment for chronic asthma. A total of 264 adult patients with chronic asthma were treated in a multi centre, randomised, double blind, placebo-controlled, parallel group Phase II pilot study, being given 0.9 or 3mg of the drug three times a day, or placebo.2 It was well tolerated and gave a dose-dependent improvement in objective pulmonary function tests, with a 10% improvement seen in those given the higher dose over placebo. No significant improvements in global symptom scores or rescue medicine use were seen, however.
It has also been given to 113 patients with symptomatic osteoarthritis of the knee in a placebo controlled trial designed to assess its effectiveness in relieving osteoarthritis pain.3 Excessive synovial fluid was removed, and subjects were given a single intra-articular dose of 90µg icatibant in 1ml saline or placebo, and monitored for six weeks. Those given the drug experienced a greater reduction in pain scores, and the use of rescue medicines was also lower in this group.
It is also being looked at in hereditary angio-oedema. Its efficacy was evaluated in an open label proof of concept trial in 15 hospitalised patients.4 They were given doses of 0.4 or 0.8mg/kg intravenously over 30 minutes, the lower dose over two hours, or 30 or 45mg subcutaneously during acute attacks. It was well tolerated, and the time to onset of symptomatic resolution was reduced to between 0.6 and 1.5 hours with the drug, compared wiyh 24-48 hours for untreated attacks. Trials continue.