Kallikrein Inhibitors (kallikrein + inhibitor)

Distribution by Scientific Domains


Selected Abstracts


Kallikrein inhibitors limit kinin B2 antagonist-induced progression of oedematous to haemorrhagic pancreatitis in rats

BRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2008
T Griesbacher
Background and purpose: Exocrine hyperstimulation with caerulein is an established model for oedematous acute pancreatitis. Prevention of oedema formation by bradykinin B2 receptor antagonists induces a progression to a haemorrhagic course in this model. We have investigated whether increased kallikrein activity in the pancreas is responsible for vascular damage and whether this could be prevented by selective kallikrein inhibitors. Experimental approach: Caerulein was infused i.v. and vascular damage was assessed by histological evaluation and determination of haemoglobin accumulation in the tissue. In addition, oedema formation, tissue and plasma kallikrein (PK) activities and the endogenous kallikrein inhibitors ,1 -antitrypsin (,1 -AT) and ,2 -macroglobulin (,2 -M) were measured. Key results: Haemorrhagic lesions induced by icatibant in caerulein-induced pancreatitis were associated with a reduction in ,1 -AT and ,2 -M in the pancreas and a concomitant augmentation of tissue kallikrein (TK) activity. The TK inhibitor VA999024 (previously FE999024), or its combination with the PK inhibitor VA999026 (previously FE999026), inhibited oedema formation to the same extent but did not induce vascular damage. Furthermore, VA999024 inhibited TK activity. When icatibant was combined with VA999024 and VA999026, progression from oedematous to haemorrhagic pancreatitis was abolished. Conclusions and implications: Reduced oedema formation by B2 antagonists prevented influx of endogenous kallikrein inhibitors and led to an excessive activity of kallikrein in the pancreas leading to vascular damage. This can be prevented by a combined inhibition of both tissue-type and plasma-type kallikrein. Kallikrein inhibitors thus should be further evaluated for their therapeutic potential in preventing haemorrhagic lesions in acute pancreatitis. British Journal of Pharmacology (2008) 155, 865,874; doi:10.1038/bjp.2008.321; published online 11 August 2008 [source]


Crystallization and preliminary X-ray analysis of a novel Kunitz-type kallikrein inhibitor from Bauhinia bauhinioides

ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 10 2005
Marcos Vicente de A. S. Navarro
A Kunitz-type protease inhibitor (BbKI) found in Bauhinia bauhinioides seeds has been overexpressed in Escherichia coli and crystallized at 293,K using PEG 4000 as the precipitant. X-ray diffraction data have been collected to 1.87, resolution using an in-house X-ray generator. The crystals of the recombinant protein (rBbKI) belong to the orthorhombic space group P212121, with unit-cell parameters a = 46.70, b = 64.14, c = 59.24,. Calculation of the Matthews coefficient suggests the presence of one monomer of rBbKI in the asymmetric unit, with a corresponding solvent content of 51% (VM = 2.5,3,Da,1). Iodinated crystals were prepared and a derivative data set was also collected at 2.1, resolution. Crystals soaked for a few seconds in a cryogenic solution containing 0.5,M NaI were found to be reasonably isomorphous to the native crystals. Furthermore, the presence of iodide anions could be confirmed in the NaI-derivatized crystal. Data sets from native and derivative crystals are being evaluated for use in crystal structure determination by means of the SIRAS (single isomorphous replacement with anomalous scattering) method. [source]


C1 inhibitor deficiency: consensus document

CLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2005
M. M. Gompels
Summary We present a consensus document on the diagnosis and management of C1 inhibitor deficiency, a syndrome characterized clinically by recurrent episodes of angio-oedema. In hereditary angio-oedema, a rare autosomal dominant condition, C1 inhibitor function is reduced due to impaired transcription or production of non-functional protein. The diagnosis is confirmed by the presence of a low serum C4 and absent or greatly reduced C1 inhibitor level or function. The condition can cause fatal laryngeal oedema and features indistinguishable from gastrointestinal tract obstruction. Attacks can be precipitated by trauma, infection and other stimulants. Treatment is graded according to response and the clinical site of swelling. Acute treatment for severe attack is by infusion of C1 inhibitor concentrate and for minor attack attenuated androgens and/or tranexamic acid. Prophylactic treatment is by attenuated androgens and/or tranexamic acid. There are a number of new products in trial, including genetically engineered C1 esterase inhibitor, kallikrein inhibitor and bradykinin B2 receptor antagonist. Individual sections provide special advice with respect to diagnosis, management (prophylaxis and emergency care), special situations (childhood, pregnancy, contraception, travel and dental care) and service specification. [source]


Kallikrein inhibitors limit kinin B2 antagonist-induced progression of oedematous to haemorrhagic pancreatitis in rats

BRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2008
T Griesbacher
Background and purpose: Exocrine hyperstimulation with caerulein is an established model for oedematous acute pancreatitis. Prevention of oedema formation by bradykinin B2 receptor antagonists induces a progression to a haemorrhagic course in this model. We have investigated whether increased kallikrein activity in the pancreas is responsible for vascular damage and whether this could be prevented by selective kallikrein inhibitors. Experimental approach: Caerulein was infused i.v. and vascular damage was assessed by histological evaluation and determination of haemoglobin accumulation in the tissue. In addition, oedema formation, tissue and plasma kallikrein (PK) activities and the endogenous kallikrein inhibitors ,1 -antitrypsin (,1 -AT) and ,2 -macroglobulin (,2 -M) were measured. Key results: Haemorrhagic lesions induced by icatibant in caerulein-induced pancreatitis were associated with a reduction in ,1 -AT and ,2 -M in the pancreas and a concomitant augmentation of tissue kallikrein (TK) activity. The TK inhibitor VA999024 (previously FE999024), or its combination with the PK inhibitor VA999026 (previously FE999026), inhibited oedema formation to the same extent but did not induce vascular damage. Furthermore, VA999024 inhibited TK activity. When icatibant was combined with VA999024 and VA999026, progression from oedematous to haemorrhagic pancreatitis was abolished. Conclusions and implications: Reduced oedema formation by B2 antagonists prevented influx of endogenous kallikrein inhibitors and led to an excessive activity of kallikrein in the pancreas leading to vascular damage. This can be prevented by a combined inhibition of both tissue-type and plasma-type kallikrein. Kallikrein inhibitors thus should be further evaluated for their therapeutic potential in preventing haemorrhagic lesions in acute pancreatitis. British Journal of Pharmacology (2008) 155, 865,874; doi:10.1038/bjp.2008.321; published online 11 August 2008 [source]