The Experts below are selected from a list of 267 Experts worldwide ranked by ideXlab platform
Julie Chao - One of the best experts on this subject based on the ideXlab platform.
-
novel roles of kallistatin a specific tissue Kallikrein Inhibitor in vascular remodeling
Biological Chemistry, 2001Co-Authors: Julie Chao, Li Mei Chen, Robert Q Miao, Vincent C Chen, Lee ChaoAbstract:We have purified, cloned and characterized kallistatin, a tissue Kallikrein-binding protein (KBP) in humans and rodents. Kallistatin is a unique serine proteinase Inhibitor (serpin) with Phe-Phe residues at the P2 and P1 positions. Structural and functional analysis of kallistatin by site-directed mutagenesis and protein engineering indicate that wild-type kallistatin is selective for tissue Kallikrein. Kallistatin is expressed and localized in endothelial and smooth muscle cells of blood vessels and has multiple roles in vascular function independent of the tissue Kallikrein-kinin system. First, kallistatin induces vasorelaxation of isolated aortic rings and reduces renal perfusion pressure in isolated rat kidneys. Transgenic mice overexpressing rat kallistatin are hypotensive, and adenovirus-mediated gene delivery of human kallistatin attenuates blood pressure rise in spontaneously hypertensive rats. Second, kallistatin stimulates the proliferation and migration of vascular smooth muscle cells in vitro and neointima formation in balloon-injured rat arteries. Third, kallistatin inhibits the proliferation, migration and adhesion of endothelial cells in vitro and angiogenesis in the rat model of hindlimb ischemia. These results demonstrate novel roles of kallistatin in blood pressure regulation and vascular remodeling.
-
A synthetic tissue Kallikrein Inhibitor suppresses cancer cell invasiveness
The American journal of pathology, 2001Co-Authors: William C. Wolf, Lee Chao, D. Michael Evans, Julie ChaoAbstract:Serine proteinases modulate the interaction of tumor cells with extracellular matrix components during extravasation and metastasis. The serine proteinase tissue Kallikrein has been previously demonstrated in several human adenocarcinomas, and we presently report the localization of immunoreactive Kallikrein and its mRNA in pancreatic adenocarcinoma. In addition, a synthetic peptide-based Inhibitor specific for tissue Kallikrein (FE999024) was used in our studies to explore a possible role for Kallikrein in cancer cell invasiveness. Matrigel invasion assays were performed with a human breast-cancer cell line, MDA-MB-231, which expresses tissue Kallikrein in culture. In the presence of FE999024 invasion through Matrigel was inhibited in a dose-dependent manner to a maximum of 39%. We also developed a novel ex vivo assay in which breast cancer cells are infused into the pulmonary circulation of artificially ventilated explanted rat lungs. At intervals up to 6 hours after infusion pulmonary invasion was quantified by bronchial alveolar lavage to recover human cancer cells from the airspace. Invading cells in the lung interstitium were also quantified after immunohistochemistry with a monoclonal antibody specific for human cytokeratin 18. The synthetic Kallikrein Inhibitor attenuates breast cancer cell invasion into the airspace by 33% when quantified by lavage recovery and up to 34% as quantified in the lung interstitium by cytokeratin 18 immunostaining. Our results indicate tissue Kallikrein may participate in the invasion and metastasis of human adenocarcinomas. The newly developed explanted rodent lung assay should be useful for the study of cancer cells, neutrophils, or other extravasating cells.
-
kallistatin a novel human tissue Kallikrein Inhibitor levels in body fluids blood cells and tissues in health and disease
Journal of Laboratory and Clinical Medicine, 1996Co-Authors: Julie Chao, Lee Chao, Alvin H Schmaier, Li Mei Chen, Zhirong YangAbstract:Kallistatin, a human serine proteinase Inhibitor, is a newly identified tissue Kallikrein Inhibitor. It binds strongly to tissue Kallikrein but weakly to other serine proteinases such as chymotrypsin and elastase. The tissue distribution and changes in kallistatin levels in human diseases were characterized by using specific monoclonal and polyclonal antibodies against kallistatin. Kallistatin antigen levels in blood cells, fluids, and tissues measured with a specific enzyme-linked immunosorbent assay showed displacement curves that were parallel with those in purified kallistatin, indicating their immunologic identity. Expression of kallistatin mRNA in platelets, neutrophils, lymphocytes, monocytes, endothelial cells, hepatocytes, and colon and prostate carcinoma cells was identified by reverse transcription-polymerase chain reaction followed by Southern blot analysis. Plasma kallistatin concentration was 22.1 ± 3.5 μg/ml in 30 normal subjects and 21.1 ± 3.8 μg/ml in 5 patients with C1 Inhibitor deficiency. A significantly reduced kallistatin level (7.2 ± 2.5 μg/ml, p < 0.001) was seen in plasma samples from 9 patients with liver disease and 10 patients with sepsis (7.7 ± 3.5 μg/ml, p < 0.001). Further, kallistatin levels in 10 women taking oral contraceptives (19.8 ± 3.8 μg/ml) and 21 pregnant women (14.9 ± 3.3 μg/ml) were significantly lower than those seen in healthy individuals. These data suggest that kallistatin is found in plasma, is produced mostly in the liver, and can be consumed during sepsis. Its consumption in sepsis may indicate a protective role to prevent blood pressure lowering.
-
High level expression of human tissue Kallikrein in the circulation induces hypotension in transgenic mice.
Immunopharmacology, 1996Co-Authors: Qing Song, Julie Chao, Lee ChaoAbstract:Abstract In order to create an animal model expressing a high level of tissue Kallikrein in the circulation, the human tissue Kallikrein gene was placed under the control of a mouse albumin enhancer and promoter to target its expression to liver. Three lines of transgenic mice carrying the human tissue Kallikrein gene were established. The major site of human tissue Kallikrein synthesis was identified in the liver of transgenic mice, and a high level of human tissue Kallikrein was secreted into the mouse circulation. The systolic blood pressures of these transgenic mice are about 15–20 mmHg lower than that of the control mice. Administration of aprotinin, a potent tissue Kallikrein Inhibitor, restored normal blood pressure in these animals. These studies show that a high level of foreign tissue Kallikrein in the circulation plays a role in blood pressure regulation
-
Tissue Kallikrein Inhibitors in mammals.
Immunopharmacology, 1996Co-Authors: Julie Chao, Karl X. Chai, Lee ChaoAbstract:Abstract We have discovered, purified and cloned a new Kallikrein-binding protein (KBP or kallistatin) from humans and rodents. Kallistatins are members of the serine proteinase Inhibitor (serpin) superfamily. They are acidic glycoproteins with molecular masses of 58–62 kDa and p I values of 4.6–5.2. Kallistatin forms a SDS-stable complex with tissue Kallikrein and inhibits Kallikrein's activities. Human kallistatin has a unique cleavage site with Phe-Phe-Ser at the P2-P1-P-1 positions. The protein sequence of mature human kallistatin shares 44–46% identity with other serpins such as human α 1 -antitrypsin, protein C Inhibitor and rat Kallikrein-binding protein. The kallistatin genes display the typical five exon-four intron serpin gene structure. The human kallistatin gene is localized on chromosome 14q31–32.1 and the RKBP gene is on chromosome 6. Kallistatin is evolutionarily diverse but functionally conserved in mammalian species. This overview summarizes the biochemistry, molecular biology and potential physiology and/or pathophysiology of this new tissue Kallikrein Inhibitor.
Lee Chao - One of the best experts on this subject based on the ideXlab platform.
-
novel roles of kallistatin a specific tissue Kallikrein Inhibitor in vascular remodeling
Biological Chemistry, 2001Co-Authors: Julie Chao, Li Mei Chen, Robert Q Miao, Vincent C Chen, Lee ChaoAbstract:We have purified, cloned and characterized kallistatin, a tissue Kallikrein-binding protein (KBP) in humans and rodents. Kallistatin is a unique serine proteinase Inhibitor (serpin) with Phe-Phe residues at the P2 and P1 positions. Structural and functional analysis of kallistatin by site-directed mutagenesis and protein engineering indicate that wild-type kallistatin is selective for tissue Kallikrein. Kallistatin is expressed and localized in endothelial and smooth muscle cells of blood vessels and has multiple roles in vascular function independent of the tissue Kallikrein-kinin system. First, kallistatin induces vasorelaxation of isolated aortic rings and reduces renal perfusion pressure in isolated rat kidneys. Transgenic mice overexpressing rat kallistatin are hypotensive, and adenovirus-mediated gene delivery of human kallistatin attenuates blood pressure rise in spontaneously hypertensive rats. Second, kallistatin stimulates the proliferation and migration of vascular smooth muscle cells in vitro and neointima formation in balloon-injured rat arteries. Third, kallistatin inhibits the proliferation, migration and adhesion of endothelial cells in vitro and angiogenesis in the rat model of hindlimb ischemia. These results demonstrate novel roles of kallistatin in blood pressure regulation and vascular remodeling.
-
A synthetic tissue Kallikrein Inhibitor suppresses cancer cell invasiveness
The American journal of pathology, 2001Co-Authors: William C. Wolf, Lee Chao, D. Michael Evans, Julie ChaoAbstract:Serine proteinases modulate the interaction of tumor cells with extracellular matrix components during extravasation and metastasis. The serine proteinase tissue Kallikrein has been previously demonstrated in several human adenocarcinomas, and we presently report the localization of immunoreactive Kallikrein and its mRNA in pancreatic adenocarcinoma. In addition, a synthetic peptide-based Inhibitor specific for tissue Kallikrein (FE999024) was used in our studies to explore a possible role for Kallikrein in cancer cell invasiveness. Matrigel invasion assays were performed with a human breast-cancer cell line, MDA-MB-231, which expresses tissue Kallikrein in culture. In the presence of FE999024 invasion through Matrigel was inhibited in a dose-dependent manner to a maximum of 39%. We also developed a novel ex vivo assay in which breast cancer cells are infused into the pulmonary circulation of artificially ventilated explanted rat lungs. At intervals up to 6 hours after infusion pulmonary invasion was quantified by bronchial alveolar lavage to recover human cancer cells from the airspace. Invading cells in the lung interstitium were also quantified after immunohistochemistry with a monoclonal antibody specific for human cytokeratin 18. The synthetic Kallikrein Inhibitor attenuates breast cancer cell invasion into the airspace by 33% when quantified by lavage recovery and up to 34% as quantified in the lung interstitium by cytokeratin 18 immunostaining. Our results indicate tissue Kallikrein may participate in the invasion and metastasis of human adenocarcinomas. The newly developed explanted rodent lung assay should be useful for the study of cancer cells, neutrophils, or other extravasating cells.
-
kallistatin a novel human tissue Kallikrein Inhibitor levels in body fluids blood cells and tissues in health and disease
Journal of Laboratory and Clinical Medicine, 1996Co-Authors: Julie Chao, Lee Chao, Alvin H Schmaier, Li Mei Chen, Zhirong YangAbstract:Kallistatin, a human serine proteinase Inhibitor, is a newly identified tissue Kallikrein Inhibitor. It binds strongly to tissue Kallikrein but weakly to other serine proteinases such as chymotrypsin and elastase. The tissue distribution and changes in kallistatin levels in human diseases were characterized by using specific monoclonal and polyclonal antibodies against kallistatin. Kallistatin antigen levels in blood cells, fluids, and tissues measured with a specific enzyme-linked immunosorbent assay showed displacement curves that were parallel with those in purified kallistatin, indicating their immunologic identity. Expression of kallistatin mRNA in platelets, neutrophils, lymphocytes, monocytes, endothelial cells, hepatocytes, and colon and prostate carcinoma cells was identified by reverse transcription-polymerase chain reaction followed by Southern blot analysis. Plasma kallistatin concentration was 22.1 ± 3.5 μg/ml in 30 normal subjects and 21.1 ± 3.8 μg/ml in 5 patients with C1 Inhibitor deficiency. A significantly reduced kallistatin level (7.2 ± 2.5 μg/ml, p < 0.001) was seen in plasma samples from 9 patients with liver disease and 10 patients with sepsis (7.7 ± 3.5 μg/ml, p < 0.001). Further, kallistatin levels in 10 women taking oral contraceptives (19.8 ± 3.8 μg/ml) and 21 pregnant women (14.9 ± 3.3 μg/ml) were significantly lower than those seen in healthy individuals. These data suggest that kallistatin is found in plasma, is produced mostly in the liver, and can be consumed during sepsis. Its consumption in sepsis may indicate a protective role to prevent blood pressure lowering.
-
High level expression of human tissue Kallikrein in the circulation induces hypotension in transgenic mice.
Immunopharmacology, 1996Co-Authors: Qing Song, Julie Chao, Lee ChaoAbstract:Abstract In order to create an animal model expressing a high level of tissue Kallikrein in the circulation, the human tissue Kallikrein gene was placed under the control of a mouse albumin enhancer and promoter to target its expression to liver. Three lines of transgenic mice carrying the human tissue Kallikrein gene were established. The major site of human tissue Kallikrein synthesis was identified in the liver of transgenic mice, and a high level of human tissue Kallikrein was secreted into the mouse circulation. The systolic blood pressures of these transgenic mice are about 15–20 mmHg lower than that of the control mice. Administration of aprotinin, a potent tissue Kallikrein Inhibitor, restored normal blood pressure in these animals. These studies show that a high level of foreign tissue Kallikrein in the circulation plays a role in blood pressure regulation
-
Tissue Kallikrein Inhibitors in mammals.
Immunopharmacology, 1996Co-Authors: Julie Chao, Karl X. Chai, Lee ChaoAbstract:Abstract We have discovered, purified and cloned a new Kallikrein-binding protein (KBP or kallistatin) from humans and rodents. Kallistatins are members of the serine proteinase Inhibitor (serpin) superfamily. They are acidic glycoproteins with molecular masses of 58–62 kDa and p I values of 4.6–5.2. Kallistatin forms a SDS-stable complex with tissue Kallikrein and inhibits Kallikrein's activities. Human kallistatin has a unique cleavage site with Phe-Phe-Ser at the P2-P1-P-1 positions. The protein sequence of mature human kallistatin shares 44–46% identity with other serpins such as human α 1 -antitrypsin, protein C Inhibitor and rat Kallikrein-binding protein. The kallistatin genes display the typical five exon-four intron serpin gene structure. The human kallistatin gene is localized on chromosome 14q31–32.1 and the RKBP gene is on chromosome 6. Kallistatin is evolutionarily diverse but functionally conserved in mammalian species. This overview summarizes the biochemistry, molecular biology and potential physiology and/or pathophysiology of this new tissue Kallikrein Inhibitor.
Maria Luiza Vilela Oliva - One of the best experts on this subject based on the ideXlab platform.
-
structure of bbki a disulfide free plasma Kallikrein Inhibitor
Acta Crystallographica Section F-structural Biology and Crystallization Communications, 2015Co-Authors: Dongwen Zhou, Marlon Vilela De Brito, Maria Luiza Vilela Oliva, Daiane Hansen, Ivan G Shabalin, Alla Gustchina, Debora F Vieira, Ana Paula Ulian De Araujo, Alexander WlodawerAbstract:A serine protease Inhibitor from Bauhinia bauhinioides (BbKI) belongs to the Kunitz family of plant Inhibitors, which are common in plant seeds. BbKI does not contain any disulfides, unlike most other members of this family. It is a potent Inhibitor of plasma Kallikrein, in addition to other serine proteases, and thus exhibits antithrombotic activity. A high-resolution crystal structure of recombinantly expressed BbKI was determined (at 1.4 A resolution) and was compared with the structures of other members of the family. Modeling of a complex of BbKI with plasma Kallikrein indicates that changes in the local structure of the reactive loop that includes the specificity-determining Arg64 are necessary in order to explain the tight binding. An R64A mutant of BbKI was found to be a weaker Inhibitor of plasma Kallikrein, but was much more potent against plasmin, suggesting that this mutant may be useful for preventing the breakup of fibrin and maintaining clot stability, thus preventing excessive bleeding.
-
conformational and biological properties of bauhinia bauhinioides Kallikrein Inhibitor fragments with bradykinin like activities
Journal of Peptide Science, 2015Co-Authors: Flavio Lopes Alves, Maria Luiza Vilela Oliva, Antonio MirandaAbstract:Proteinase Inhibitors extracted form medicinal plants are an interesting source of new drugs. Modifications in the structure of some of this kind of macromolecules could also lead to compounds of interesting biological properties. In this work, we synthesized and tested one fragment containing the reactive site of the Bauhinia bauhinioides Kallikrein Inhibitor (BbKI), denoted BbKI51–62, and a related analog (P2) in which a proline residue was inserted in order to mimic the N-terminal region of the bradykinin molecule. The related retro-inverso counterparts Ri-BbKI51–62 and Ri-P2 were also included. The ability of these peptides to induce contraction of stomach fundus isolated from mouse was evaluated as well as their capability to induce calcium release from a cell culture of smooth muscle from guinea pig ileum. The conformational properties of the peptides were evaluated by circular dichroism and their resistance to enzymatic degradation by exposure to human blood plasma. Our results show that neither the parent BbKI51–62 nor its Ri-BbKI51–62 analog exhibit bradykinin-like activity, although the retro-inverso isomer was resistant to blood plasma degradation. On the other hand, the peptides P2 and Ri-P2 presented contractile activities on gastric smooth muscle from stomach fundus possibly by acting via B-2 receptor. Both compounds also induce calcium release from guinea pig ileum muscle cells in a manner similar to bradykinin. Moreover, both compounds also inhibited porcine pancreatic Kallikrein. However, conformational analysis did not reveal any direct correlation between structure and biological effects. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.
-
The Kallikrein Inhibitor from Bauhinia bauhinioides (BbKI) shows antithrombotic properties in venous and arterial thrombosis models.
Thrombosis research, 2014Co-Authors: Marlon Vilela De Brito, Cleide De Oliveira, Bruno R. Salu, Sonia A. De Andrade, Paula M. D. Malloy, Ana C. Sato, Cristina P. Vicente, Misako U. Sampaio, Francisco Humberto De Abreu Maffei, Maria Luiza Vilela OlivaAbstract:The Bauhinia bauhinioides Kallikrein Inhibitor (BbKI) is a Kunitz-type serine peptidase Inhibitor of plant origin that has been shown to impair the viability of some tumor cells and to feature a potent Inhibitory activity against human and rat plasma Kallikrein (Kiapp 2.4 nmol/L and 5.2 nmol/L, respectively). This Inhibitory activity is possibly responsible for an effect on hemostasis by prolonging activated partial thromboplastin time (aPTT). Because the association between cancer and thrombosis is well established, we evaluated the possible antithrombotic activity of this protein in venous and arterial thrombosis models. Vein thrombosis was studied in the vena cava ligature model in Wistar rats, and arterial thrombosis in the photochemical induced endothelium lesion model in the carotid artery of C57 black 6 mice. BbKI at a concentration of 2.0 mg/kg reduced the venous thrombus weight by 65% in treated rats in comparison to rats in the control group. The Inhibitor prolonged the time for total artery occlusion in the carotid artery model mice indicating that this potent plasma Kallikrein Inhibitor prevented thrombosis.
-
effect of bauhinia bauhinioides Kallikrein Inhibitor on endothelial proliferation and intracellular calcium concentration
European Review for Medical and Pharmacological Sciences, 2014Co-Authors: Mehmet Bilgin, Maria Luiza Vilela Oliva, K M Burgazli, A Rafiq, M Mericliler, C Neuhof, Mariana S Parahuleva, Nedim Soydan, O Doerr, Yaser AbdallahAbstract:OBJECTIVES : Proteinase Inhibitors act as a defensive system against predators e.g. in - sects, in plants. Bauhinia bauhinioides Kallikrein Inhibitor (BbKI) is a serine proteinase Inhibitor, iso - lated from seeds of Bauhinia bauhinioides and is structurally similar to plant Kunitz-type Inhibitors but lacks disulfide bridges. In this study we evalu - ated the antiproliferative effect of BbKI on endothe - lial cells and its impact on changes in membrane potential and intracellular calcium. MATERIALS AND METHODS: HUVEC prolifer - ation was significantly reduced by incubation with BbKI 50 and 100 µM 12% and 13%. Further - more, BbKI (100 µM) exposure caused a signifi - cant increase in intracellular Ca 2+ concentration by 35% as compared to untreated control. RESULTS: The intracellular rise in calcium was not affected by the absence of extracellular cal - cium. BBKI also caused a significant change in the cell membrane potential but the antiprolifera - tive effect was independent of changes in mem - brane potential. CONCLUSIONS: BBKI has an antiproliferative effect on HUVEC, which is independent of the changes in membrane potential, and it causes an increase in intracellular Ca 2+ .
-
plant proteinase from bauhinia bauhinioides Kallikrein Inhibitor bbki attenuates inflammation and remodelling induced by elastase in mice
European Respiratory Journal, 2013Co-Authors: Edna A Leick, Maria Luiza Vilela Oliva, Bruno T M Oliveira, Rafael Almeidareis, Leandro V Oliva, Osmar A Theodoro, Carla Maximo Prado, Milton A Martins, Iolanda F L C TiberioAbstract:Aims: To evaluate if a plant Kunitz proteinase Inhibitor BbKI contributes to inactivation of elastase-induced inflammatory and extracellular matrix remodelling alterations. Methods: C57Bl6 mice received elastase (50ml/animal/intratracheal-E-group) or saline (Ve-group). Mice were treated with BbKI (2mg/kg) on days 1, 14, 21 after elastase instillation (I-E group) or saline instillation (I-Ve group). On day 30 mice were anesthetized, mechanically ventilated, lungs were removed and we quantified neutrophils, positive cells for MMP-9, MMP-12, TNF-a, MAC-2, TIMP, IL8, MUC5, iNOS, eNOS and volume fraction of elastic and collagen fibers and PGF2alpha in alveolar septa and airways. Results : In E-group, there was an increase of neutrophils, MMP-9, MMP-12, TNF-a, MAC-2, TIMP, IL8, MUC5, iNOS, eNOS, elastic and collagen fibers and isoprostanes in alveolar and/or airways compared to controls (p<0.05). In I-E group, there was a reduction in alveolar septa of neutrophils, positive cells for MMP-9, MMP-12, TNF-a, MAC-2, TIMP1, IL8, iNOS, eNOS, PGF2alpha, collagen and elastic fibers compared to E-group. Considering airways of I-E group, there was a decrease of neutrophils, positive cells for MMP-9, MMP-12, TNF-a, TIMP1, IL8, MUC5, iNOS, eNOS, PGF2alpha, elastic and collagen fibers compared to E-group (p<0.05). Conclusions: This proteinase Inhibitor ( BbKI ) reduced elastase-induced pulmonary inflammatory and extracellular matrix remodeling alterations induced by elastase and this Inhibitor may contribute as potential therapeutic tool for COPD management. Financial Support : FAPESP, CNPq, LIM-20 HC-FMUSP.
C A M Sampaio - One of the best experts on this subject based on the ideXlab platform.
-
bauhinia bauhinioides plasma Kallikrein Inhibitor interaction with synthetic peptides and fluorogenic peptide substrates related to the reactive site sequence
Current Medicinal Chemistry, 2001Co-Authors: Maria Luiza Vilela Oliva, Misako U. Sampaio, C R Mendes, E M Santomaurovaz, Maria A Juliano, Reinhart Mentele, Ennes A Auerswald, C A M SampaioAbstract:A serine proteinase Inhibitor was purified from Bauhinia bauhinioides seeds after extraction with 0.15M NaCl by ion-exchange column chromatography on DEAE-Sephadex, gel filtration on Superose 12 column, Mono Q chromatography or alternatively by affinity chromatography on trypsin- Sepharose. The Inhibitor is a single polypeptide chain with molecular mass 20 kDa by gel filtration on Superose 12, but was resolved into two peaks by ion - exchange chromatography on Mono Q (FPLC system). The main eluted peak inhibits trypsin (Ki = 0.6 nM), plasma Kallikrein (Ki = 0.35 nM), plasmin (Ki = 33.1 nM), and weakly chymotrypsin (Ki = 2,700 nM), being the most effective plasma Kallikrein Inhibitor isolated from Bauhinia seeds. Therefore, it was denominated Bauhinia bauhinioides Kallikrein Inhibitor (BbKI). Activity is thermolabile and on trypsin inhibition optimum pH is 8.0. BbKI displays high homology to other plant Kunitz Inhibitors, except for the absence of disulfide bridges, and the only cysteine residue is at the C-terminal position (residue 154) characterizes a distinct member of the Kunitz family. The affinity of the Inhibitor to trypsin was confirmed by adsorption to trypsin-Sepharose resin and by isolation of the trypsin-Inhibitor complex by gel filtration. Peptides with variations around the reactive site of BbKI (GLPVRFESPLRINIIKESY) were synthesized containing a quenched fluorogenic group. Trypsin but not plasma Kallikrein substrates, these peptides strongly inhibited plasma Kallikrein.
Timothy J. Craig - One of the best experts on this subject based on the ideXlab platform.
-
a review of Kallikrein Inhibitor lanadelumab in hereditary angioedema
Immunotherapy, 2019Co-Authors: Gloria Hwang, Ansh Johri, Timothy J. CraigAbstract:Hereditary angioedema with C1 esterase Inhibitor deficiency is a rare disorder characterized by unpredictable swelling of the face, larynx and gastrointestinal tract. Kallikreins are serine proteases that cleave kininogens to produce bradykinin leading to inflammation. A new prophylactic drug is lanadelumab (DX-2930, SHP-643), a recombinant, fully human IgG1 monoclonal antibody Kallikrein Inhibitor. Pharmacokinetics show a half-life of 14 days with a dose-dependent effect. Completed trials for lanadelumab include two Phase III studies with updated efficacy in preventing angioedema in hereditary angioedema patients. Ongoing data show the safety of the targeted therapy along with less frequent administration requirements. Information on long-term safety is still needed, as well as, further studies on the correlation of subcutaneous administered dosing requirements and severity of side effects.
-
oral plasma Kallikrein Inhibitor bcx7353 for treatment of hereditary angioedema
Immunotherapy, 2019Co-Authors: Jacqueline R Hwang, Ansh Johri, Gloria Hwang, Timothy J. CraigAbstract:Hereditary angioedema (HAE) is rare disorder caused by a SERPING1 gene mutation that triggers severe swelling of the skin and upper airway. Treatment options for HAE with deficient and dysfunctional C1-Inhibitor are expanding to include small-molecule drugs that inhibit protein interactions in the Kallikrein-kinin system. Discovered by BioCryst Pharmaceuticals, BCX7353 is a synthetic, once-daily, small molecule drug that can be taken as an oral capsule to treat HAE attacks and for prophylaxis. This article will summarize recent and current BCX7353 clinical trials. Overall, results indicate BCX7353 is a promising form of therapy with a rapid 1 h onset of action, long duration of action, and acceptable tolerance.
-
Recombinant human C1 esterase Inhibitor for the treatment of hereditary angioedema due to C1 Inhibitor deficiency (C1-INH-HAE).
Expert review of clinical immunology, 2015Co-Authors: Geetika Sabharwal, Timothy J. CraigAbstract:The lack of C1 Inhibitor function that results in excessive production of bradykinin causing the angioedema seen in hereditary angioedema (HAE) is well established. Several drugs have been developed to treat and prevent attacks in patients suffering from HAE due to C1 Inhibitor deficiency (C1-INH-HAE). Plasma-derived C1INH has been used to replace the deficiency of C1 Inhibitor (C1INH) and has been approved for both treatment of attacks and for prophylactic therapy to prevent attacks. Plasma Kallikrein Inhibitor (ecallantide) and bradykinin receptor antagonist (icatibant) are both effective for treatment of acute attacks, but their short half-life limits the use for prophylaxis. Androgens, in particular danazol, are effective for long-term prophylaxis, but adverse event profile can limit its use. Recombinant C1 Inhibitor derived from transgenic rabbits has recently been approved for use in treatment of C1-INH-HAE attacks and is effective and appears safe with minimal adverse event profile.
-
Overview of ecallantide in the treatment of hereditary angioedema types I and II
Therapy, 2010Co-Authors: Erin Banta, Timothy J. CraigAbstract:Hereditary angioedema is a rare disease characterized by unpredictable attacks of swelling in any anatomic location. Hereditary angioedema attacks lead to significant morbidity and can occasionally cause mortality. Treatment for acute attacks includes intravenous C1 esterase Inhibitor replacement and, in Europe, subcutaneous bradykinin Inhibitor (icatibant). In December 2009, a new medication aimed at the bradykinin cascade called ecallantide received approval from the US FDA for the treatment of acute attacks of hereditary angioedema. Ecallantide is a 60-amino acid recombinant protein that is a potent and specific plasma Kallikrein Inhibitor. Ecallantide is subcutaneously administered and not plasma derived. In the Phase III EDEMA3 and EDEMA4 studies, subjects treated with ecallantide had statistically significant evidence of clinical improvement at 4 and 24 h when compared with subjects treated with placebo. Ecallantide is an alternative to C1 esterase Inhibitor and icatibant for the treatment of acute ...
