Potential clinical applications of kinin receptor ligands

Type of Agent Application Investigational Status References
B2 receptor agonists
   Labradimil Transient opening of the blood-brain barrier (adjuvant to chemotherapy of brain tumors) Extensive animal studies performed Emerich et al., 2001
   Lys-BK Additive to vaccines to skew the immune response from humoral (TH2) to cellular responses (TH1) Hypothesis supported by animal data Aliberti et al., 2003
   FR190997, others Renal, cardiac protection, and hypertension, via endothelial mediator release Speculative; unfavorable risk to benefit ratio probable Heitsch, 2002
B1 receptor agonists
   Sar-[d-Phe8]-des-Arg9-BK Angiogenesis, vasculogenesis in severe ischemic disease Speculative; supported by animal data Emanueli et al., 2002
B2 receptor antagonists
   Icatibant, several others Inflammatory pain (hyperalgesia) Abundantly supported by animal studies Steranka et al., 1988; Perkins et al., 1993; Burgess et al., 2000
   Icatibant, others Inflammatory edema Supported by many animal studies Uknis et al., 2002; Samadfam et al., 2000
   LF16-0687, deltibant Brain edema (post-traumatic or secondary to stoke) Mixed results of a limited clinical trial of deltibant for head trauma; extensive animal data supporting LF16-0687; the later drug is being clinically evaluated for head trauma Narotam et al., 1998; Kaplanski et al., 2002; Zausigner et al., 2002
   Icatibant Hereditary angioedema Active in a mouse model (C1 inhibitor gene knockout); Icatibant being clinically evaluated for this indication, as well as for ascites secondary to liver cirrhosis (Jerini AG) Han et al., 2002
   Icatibant Allergic asthma, rhinitis Objective and protracted anti-inflammatory effects shown in humans following local application to mucosa Akbary et al., 1996; Turner et al., 2001
   Deltibant Sepsis Disappointing results of a clinical trial Fein et al., 1997
B1 receptor antagonists
   [Leu8]-des-Arg9-BK, others Inflammatory pain (hyperalgesia); effect may extend to neuropathic pain, wind-up, and viscero-visceral hyper-reflexia Abundantly supported by animal studies; may be effective during a retarded time window, relative to B2 receptor antagonists Perkins et al., 1993; Bélichard et al., 2000; Levy and Zochodne, 2000; Pesquero et al., 2000; Jaggar et al., 1998
   Lys-[Leu8]-des-Arg9-BK, others Inflammation Effects in animal models Blais et al., 2000; deBlois and Horlick, 2001
   Unspecified Epilepsy Speculative; based on the epileptogenic effect of the agonist in animal models Bregola et al., 1999
   Des-Arg10-Hoe 140 Airway allergy Benefits in a rat model; speculative in humans Huang et al., 1999; Christiansen et al., 2002
   Unspecified Sepsis Speculative; based on the counterproductive hemodynamic effect of agonist in LPS-pretreated rabbits Audet et al., 1997
Promiscuous ligands
   CU201 = B9870 Cancer Whereas both antagonists of the B1 and B2 receptors have been proposed or used in a limited manner as experimental antineoplasic agents, CU201 may be more effective in specific tumorigenic cell lines than conventional antagonists Chan et al., 2002a,b; Stewart et al., 2003