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Gregory J Gores - One of the best experts on this subject based on the ideXlab platform.
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the Caspase Inhibitor idn 6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Ali Canbay, Edwina S Baskinbey, Ariel E Feldstein, Steven F Bronk, Gregory J GoresAbstract:Liver injury is characterized by hepatocyte apoptosis and collagen-producing activated hepatic stellate cells (HSC). Hepatocyte apoptosis promotes liver injury and fibrosis, whereas activated HSC apoptosis limits hepatic fibrosis. Pharmacological inhibition of liver cell apoptosis may potentially attenuate liver injury and fibrosis by blocking hepatocyte apoptosis or promote fibrosis by permitting accumulation of activated HSCs. To ascertain the net effect of inhibiting liver cell apoptosis on liver injury, inflammation, and hepatic fibrogenesis, we examined the effect of a panCaspase inhibition IDN-6556 on these parameters in the bile duct ligated (BDL) mouse. Hepatocyte apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and immunofluorescence for active Caspases 3/7, and liver injury by histopathology and serum alanine aminotransferase (ALT) determinations. Real-time polymerase chain reaction was used to measure mRNA transcripts for markers of hepatic inflammation, HSC activation, and fibrosis. Immunohistochemistry for α-smooth muscle actin was performed to identify HSC activation. Collagen deposition was quantitated by Sirius red staining and digital imaging techniques. Hepatocyte apoptosis and liver injury (bile infarcts and serum ALT values) were reduced in IDN-6556-treated versus saline-treated 3-day BDL mice. Markers for liver inflammation [chemokine (C-X-C) ligand 1 and macrophage inflammatory protein-2 chemokine expression] and hepatic fibrogenesis (transforming growth factor-β and collagen I expression) were also attenuated. Consistent with these data, HSC activation as assessed by α-smooth muscle actin mRNA expression and immunohistochemistry was markedly reduced in both 3- and 10-day BDL animals. Collectively, these data suggest hepatocyte apoptosis initiates cascades culminating in liver injury and fibrosis. The pan-Caspase Inhibitor IDN-6556 is a promising agent for cholestatic liver injury.
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the Caspase Inhibitor idn 6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Ali Canbay, Edwina S Baskinbey, Ariel E Feldstein, Steven F Bronk, Gregory J GoresAbstract:Liver injury is characterized by hepatocyte apoptosis and collagen-producing activated hepatic stellate cells (HSC). Hepatocyte apoptosis promotes liver injury and fibrosis, whereas activated HSC apoptosis limits hepatic fibrosis. Pharmacological inhibition of liver cell apoptosis may potentially attenuate liver injury and fibrosis by blocking hepatocyte apoptosis or promote fibrosis by permitting accumulation of activated HSCs. To ascertain the net effect of inhibiting liver cell apoptosis on liver injury, inflammation, and hepatic fibrogenesis, we examined the effect of a panCaspase inhibition IDN-6556 on these parameters in the bile duct ligated (BDL) mouse. Hepatocyte apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and immunofluorescence for active Caspases 3/7, and liver injury by histopathology and serum alanine aminotransferase (ALT) determinations. Real-time polymerase chain reaction was used to measure mRNA transcripts for markers of hepatic inflammation, HSC activation, and fibrosis. Immunohistochemistry for alpha-smooth muscle actin was performed to identify HSC activation. Collagen deposition was quantitated by Sirius red staining and digital imaging techniques. Hepatocyte apoptosis and liver injury (bile infarcts and serum ALT values) were reduced in IDN-6556-treated versus saline-treated 3-day BDL mice. Markers for liver inflammation [chemokine (C-X-C) ligand 1 and macrophage inflammatory protein-2 chemokine expression] and hepatic fibrogenesis (transforming growth factor-beta and collagen I expression) were also attenuated. Consistent with these data, HSC activation as assessed by alpha-smooth muscle actin mRNA expression and immunohistochemistry was markedly reduced in both 3- and 10-day BDL animals. Collectively, these data suggest hepatocyte apoptosis initiates cascades culminating in liver injury and fibrosis. The pan-Caspase Inhibitor IDN-6556 is a promising agent for cholestatic liver injury.
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the Caspase Inhibitor idn 6556 prevents Caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injury
Liver Transplantation, 2003Co-Authors: Shiho Natori, Hajime Higuchi, Patricia C Contreras, Gregory J GoresAbstract:Abstract Cold ischemia (CI)–warm reperfusion (WR) liver injury remains a problem in liver transplantation. CI-WR initially causes sinusoidal endothelial cell (SEC) apoptosis through a Caspase-dependent mechanism. We previously showed that the Caspase Inhibitor IDN-1965 prevents CI-WR–induced SEC apoptosis. However, this agent required to be administered to the donor, preservation solution, and recipient for efficacy. Here, we show that a second-generation Caspase Inhibitor, IDN-6556, effectively prevents CI-WR–induced SEC injury when added only to University of Wisconsin (UW) cold storage media. Rat livers were stored in UW solution for 24 hours at 4°C and reperfused for 1 hour at 37°C. Apoptosis was quantitated using terminal deoxynucleotide transferasemediated deoxyuridine triphosphate nick end labeling (TUNEL) assay and Caspase 3 activation determined by biochemical measurement and immunohistochemical analysis. Pan-Caspase Inhibitors (IDN-8066, IDN-7503, IDN-7436, IDN-1965, and IDN-6556) were applied at preischemic, cold preservation, or reperfusion periods. TUNEL-positive SEC and Caspase 3–like activity in the liver was increased by CI-WR. Three Caspase Inhibitors (IDN-8066, IDN-1965, and IDN-6556) effectively attenuated SEC apoptosis and Caspase 3 activation. The most potent Inhibitor, IDN-6556, reduced SEC apoptosis and Caspase 3 activity by 55% and 94%, respectively. Prevention of SEC apoptosis by IDN-6556 was not reduced when this agent was administered only during the cold preservation period. When added to the preservation solution, the Caspase Inhibitor IDN-6556 appears to be a feasible therapeutic agent against ischemia-reperfusion injury in liver transplantation. ( Liver Transpl 2003;9:278-284. )
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the Caspase Inhibitor idn 6556 prevents Caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injury
Liver Transplantation, 2003Co-Authors: Shiho Natori, Hajime Higuchi, Patricia C Contreras, Gregory J GoresAbstract:Cold ischemia (CI)-warm reperfusion (WR) liver injury remains a problem in liver transplantation. CI-WR initially causes sinusoidal endothelial cell (SEC) apoptosis through a Caspase-dependent mechanism. We previously showed that the Caspase Inhibitor IDN-1965 prevents CI-WR-induced SEC apoptosis. However, this agent required to be administered to the donor, preservation solution, and recipient for efficacy. Here, we show that a second-generation Caspase Inhibitor, IDN-6556, effectively prevents CI-WR-induced SEC injury when added only to University of Wisconsin (UW) cold storage media. Rat livers were stored in UW solution for 24 hours at 4 degrees C and reperfused for 1 hour at 37 degrees C. Apoptosis was quantitated using terminal deoxynucleotide transferasemediated deoxyuridine triphosphate nick end labeling (TUNEL) assay and Caspase 3 activation determined by biochemical measurement and immunohistochemical analysis. Pan-Caspase Inhibitors (IDN-8066, IDN-7503, IDN-7436, IDN-1965, and IDN-6556) were applied at preischemic, cold preservation, or reperfusion periods. TUNEL-positive SEC and Caspase 3-like activity in the liver was increased by CI-WR. Three Caspase Inhibitors (IDN-8066, IDN-1965, and IDN-6556) effectively attenuated SEC apoptosis and Caspase 3 activation. The most potent Inhibitor, IDN-6556, reduced SEC apoptosis and Caspase 3 activity by 55% and 94%, respectively. Prevention of SEC apoptosis by IDN-6556 was not reduced when this agent was administered only during the cold preservation period. When added to the preservation solution, the Caspase Inhibitor IDN-6556 appears to be a feasible therapeutic agent against ischemia-reperfusion injury in liver transplantation.
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apoptosis of sinusoidal endothelial cells occurs during liver preservation injury by a Caspase dependent mechanism
Transplantation, 1999Co-Authors: Shiho Natori, Karen L Valentino, Anu Srinivasan, Markus Selzner, Lawrence C Fritz, Pierre A Clavien, Gregory J GoresAbstract:Cold ischemia/warm reperfusion (CI/WR) liver injury remains a problem in liver transplants. Sinusoidal endothelial cells (SEC) are a target of CI/WR injury, during which they undergo apoptosis. Because Caspase proteases have been implicated in apoptosis, our aim was to determine whether liver CI/WR injury induces a Caspase-dependent apoptosis of SEC. Rat livers were stored in the University of Wisconsin (UW) solution for 24 hr at 4°C and reperfused for 1 hr at 37°C in vitro. Apoptosis was quantitated using the TUNEL assay, and Caspase 3 activation determined by immunohistochemical analysis. Rat liver orthotopic liver transplants (OLT) were also performed using livers stored for 30 hr. Terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) positive hepatocytes were rare and did not increase during CI/WR injury. In contrast, TUNEL positive SEC increased 6-fold after reperfusion of livers stored under cold ischemic conditions, compared with controls or livers stored but not reperfused. Immunohistochemical analysis demonstrated active Caspase 3 only in endothelial cells after CI/WR injury. When IDN-1965, a Caspase Inhibitor, was given i.v. to the donor animal and added to UW solution and the reperfusion media, TUNEL positive endothelial cells were reduced 63±11% (P<0.05). Similarly, the duration of survival after OLT was significantly increased in the presence of the Inhibitor. During liver CI/WR injury: 1) selective apoptosis of endothelial cells occurs; 2) Caspase 3 is activated only in endothelial cells; and 3) a Caspase Inhibitor reduces endothelial cell apoptosis and prolongs animal survival after OLT. The pharmacologic use of Caspase Inhibitors could prove useful in clinical transplantation.
Patricia C Contreras - One of the best experts on this subject based on the ideXlab platform.
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first in class pan Caspase Inhibitor developed for the treatment of liver disease
Journal of Medicinal Chemistry, 2005Co-Authors: Steven D Linton, Patricia C Contreras, Teresa Aja, Robert A Armstrong, Xu Bai, Longshiuh Chen, Ning Chen, Brett Weylan Ching, Joseluis Diaz, Craig D FisherAbstract:A series of oxamyl dipeptides were optimized for pan Caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure−activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, Inhibitors were selected for study in a murine model of α-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class Caspase Inhibitor is now the subject of two Phase II clinical trials, evaluating its safety and efficacy for use in liver disease.
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characterization of idn 6556 3 2 2 tert butyl phenylaminooxalyl amino propionylamino 4 oxo 5 2 3 5 6 tetrafluoro phenoxy pentanoic acid a liver targeted Caspase Inhibitor
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Niel C Hoglen, Longshiuh Chen, Craig D Fisher, Brad P Hirakawa, Todd Groessl, Patricia C ContrerasAbstract:The potency, efficacy, and pharmacokinetic properties of IDN-6556 (3-[2-[(2-tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid), a first-in-class Caspase Inhibitor in clinical trials for the treatment of liver diseases, were characterized in vivo in rodent models. In the mouse alpha-Fas model of liver injury, i.p. administration of IDN-6556 resulted in marked reduction of alanine aminotransferase (ALT), apoptosis, and Caspase activities at a dose of 3 mg/kg. At this dose, IDN-6556 was also effective when given up to 2 h before alpha-Fas and as late as 4 h after alpha-Fas administration. In both the alpha-Fas and d-galactosamine/lipopolysaccharide (D-Gln/LPS) model, ED(50) values in the sub-milligram per kilogram range were established after a number of routes of administration (i.p., i.v., i.m., or p.o.), ranging from 0.04 to 0.38 mg/kg. Efficacy was also demonstrated in the rat D-Gln/LPS model with 67 and 72% reductions in ALT activities after i.p. and p.o. treatment with IDN-6556 (10 mg/kg), respectively. Pharmacokinetic analysis in the rat demonstrated rapid clearance after i.v., i.p., and s.c. administration with terminal t(1/2) ranging from 46 to 51 min. Low absolute bioavailability after p.o. administration was seen (2.7-4%), but portal drug concentrations after oral administration were 3-fold higher than systemic concentrations with a 3.7-fold increase in the terminal t(1/2), indicating a significant first-pass effect. Liver concentrations remained constant after oral administration for at least a 4-h period, reaching a C(max) of 2558 ng/g liver at 120 min. Last, 51 +/- 20 and 4.9 +/- 3.4% of IDN-6556 was excreted intact in bile after i.v. and p.o. administration, respectively. This evaluation indicates that IDN-6556 has marked efficacy in models of liver disease after oral administration and thus, is an excellent candidate for the treatment of liver diseases characterized by excessive apoptosis.
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the Caspase Inhibitor idn 6556 prevents Caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injury
Liver Transplantation, 2003Co-Authors: Shiho Natori, Hajime Higuchi, Patricia C Contreras, Gregory J GoresAbstract:Abstract Cold ischemia (CI)–warm reperfusion (WR) liver injury remains a problem in liver transplantation. CI-WR initially causes sinusoidal endothelial cell (SEC) apoptosis through a Caspase-dependent mechanism. We previously showed that the Caspase Inhibitor IDN-1965 prevents CI-WR–induced SEC apoptosis. However, this agent required to be administered to the donor, preservation solution, and recipient for efficacy. Here, we show that a second-generation Caspase Inhibitor, IDN-6556, effectively prevents CI-WR–induced SEC injury when added only to University of Wisconsin (UW) cold storage media. Rat livers were stored in UW solution for 24 hours at 4°C and reperfused for 1 hour at 37°C. Apoptosis was quantitated using terminal deoxynucleotide transferasemediated deoxyuridine triphosphate nick end labeling (TUNEL) assay and Caspase 3 activation determined by biochemical measurement and immunohistochemical analysis. Pan-Caspase Inhibitors (IDN-8066, IDN-7503, IDN-7436, IDN-1965, and IDN-6556) were applied at preischemic, cold preservation, or reperfusion periods. TUNEL-positive SEC and Caspase 3–like activity in the liver was increased by CI-WR. Three Caspase Inhibitors (IDN-8066, IDN-1965, and IDN-6556) effectively attenuated SEC apoptosis and Caspase 3 activation. The most potent Inhibitor, IDN-6556, reduced SEC apoptosis and Caspase 3 activity by 55% and 94%, respectively. Prevention of SEC apoptosis by IDN-6556 was not reduced when this agent was administered only during the cold preservation period. When added to the preservation solution, the Caspase Inhibitor IDN-6556 appears to be a feasible therapeutic agent against ischemia-reperfusion injury in liver transplantation. ( Liver Transpl 2003;9:278-284. )
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the Caspase Inhibitor idn 6556 prevents Caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injury
Liver Transplantation, 2003Co-Authors: Shiho Natori, Hajime Higuchi, Patricia C Contreras, Gregory J GoresAbstract:Cold ischemia (CI)-warm reperfusion (WR) liver injury remains a problem in liver transplantation. CI-WR initially causes sinusoidal endothelial cell (SEC) apoptosis through a Caspase-dependent mechanism. We previously showed that the Caspase Inhibitor IDN-1965 prevents CI-WR-induced SEC apoptosis. However, this agent required to be administered to the donor, preservation solution, and recipient for efficacy. Here, we show that a second-generation Caspase Inhibitor, IDN-6556, effectively prevents CI-WR-induced SEC injury when added only to University of Wisconsin (UW) cold storage media. Rat livers were stored in UW solution for 24 hours at 4 degrees C and reperfused for 1 hour at 37 degrees C. Apoptosis was quantitated using terminal deoxynucleotide transferasemediated deoxyuridine triphosphate nick end labeling (TUNEL) assay and Caspase 3 activation determined by biochemical measurement and immunohistochemical analysis. Pan-Caspase Inhibitors (IDN-8066, IDN-7503, IDN-7436, IDN-1965, and IDN-6556) were applied at preischemic, cold preservation, or reperfusion periods. TUNEL-positive SEC and Caspase 3-like activity in the liver was increased by CI-WR. Three Caspase Inhibitors (IDN-8066, IDN-1965, and IDN-6556) effectively attenuated SEC apoptosis and Caspase 3 activation. The most potent Inhibitor, IDN-6556, reduced SEC apoptosis and Caspase 3 activity by 55% and 94%, respectively. Prevention of SEC apoptosis by IDN-6556 was not reduced when this agent was administered only during the cold preservation period. When added to the preservation solution, the Caspase Inhibitor IDN-6556 appears to be a feasible therapeutic agent against ischemia-reperfusion injury in liver transplantation.
Shiho Natori - One of the best experts on this subject based on the ideXlab platform.
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the Caspase Inhibitor idn 6556 prevents Caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injury
Liver Transplantation, 2003Co-Authors: Shiho Natori, Hajime Higuchi, Patricia C Contreras, Gregory J GoresAbstract:Abstract Cold ischemia (CI)–warm reperfusion (WR) liver injury remains a problem in liver transplantation. CI-WR initially causes sinusoidal endothelial cell (SEC) apoptosis through a Caspase-dependent mechanism. We previously showed that the Caspase Inhibitor IDN-1965 prevents CI-WR–induced SEC apoptosis. However, this agent required to be administered to the donor, preservation solution, and recipient for efficacy. Here, we show that a second-generation Caspase Inhibitor, IDN-6556, effectively prevents CI-WR–induced SEC injury when added only to University of Wisconsin (UW) cold storage media. Rat livers were stored in UW solution for 24 hours at 4°C and reperfused for 1 hour at 37°C. Apoptosis was quantitated using terminal deoxynucleotide transferasemediated deoxyuridine triphosphate nick end labeling (TUNEL) assay and Caspase 3 activation determined by biochemical measurement and immunohistochemical analysis. Pan-Caspase Inhibitors (IDN-8066, IDN-7503, IDN-7436, IDN-1965, and IDN-6556) were applied at preischemic, cold preservation, or reperfusion periods. TUNEL-positive SEC and Caspase 3–like activity in the liver was increased by CI-WR. Three Caspase Inhibitors (IDN-8066, IDN-1965, and IDN-6556) effectively attenuated SEC apoptosis and Caspase 3 activation. The most potent Inhibitor, IDN-6556, reduced SEC apoptosis and Caspase 3 activity by 55% and 94%, respectively. Prevention of SEC apoptosis by IDN-6556 was not reduced when this agent was administered only during the cold preservation period. When added to the preservation solution, the Caspase Inhibitor IDN-6556 appears to be a feasible therapeutic agent against ischemia-reperfusion injury in liver transplantation. ( Liver Transpl 2003;9:278-284. )
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the Caspase Inhibitor idn 6556 prevents Caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injury
Liver Transplantation, 2003Co-Authors: Shiho Natori, Hajime Higuchi, Patricia C Contreras, Gregory J GoresAbstract:Cold ischemia (CI)-warm reperfusion (WR) liver injury remains a problem in liver transplantation. CI-WR initially causes sinusoidal endothelial cell (SEC) apoptosis through a Caspase-dependent mechanism. We previously showed that the Caspase Inhibitor IDN-1965 prevents CI-WR-induced SEC apoptosis. However, this agent required to be administered to the donor, preservation solution, and recipient for efficacy. Here, we show that a second-generation Caspase Inhibitor, IDN-6556, effectively prevents CI-WR-induced SEC injury when added only to University of Wisconsin (UW) cold storage media. Rat livers were stored in UW solution for 24 hours at 4 degrees C and reperfused for 1 hour at 37 degrees C. Apoptosis was quantitated using terminal deoxynucleotide transferasemediated deoxyuridine triphosphate nick end labeling (TUNEL) assay and Caspase 3 activation determined by biochemical measurement and immunohistochemical analysis. Pan-Caspase Inhibitors (IDN-8066, IDN-7503, IDN-7436, IDN-1965, and IDN-6556) were applied at preischemic, cold preservation, or reperfusion periods. TUNEL-positive SEC and Caspase 3-like activity in the liver was increased by CI-WR. Three Caspase Inhibitors (IDN-8066, IDN-1965, and IDN-6556) effectively attenuated SEC apoptosis and Caspase 3 activation. The most potent Inhibitor, IDN-6556, reduced SEC apoptosis and Caspase 3 activity by 55% and 94%, respectively. Prevention of SEC apoptosis by IDN-6556 was not reduced when this agent was administered only during the cold preservation period. When added to the preservation solution, the Caspase Inhibitor IDN-6556 appears to be a feasible therapeutic agent against ischemia-reperfusion injury in liver transplantation.
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apoptosis of sinusoidal endothelial cells occurs during liver preservation injury by a Caspase dependent mechanism
Transplantation, 1999Co-Authors: Shiho Natori, Karen L Valentino, Anu Srinivasan, Markus Selzner, Lawrence C Fritz, Pierre A Clavien, Gregory J GoresAbstract:Cold ischemia/warm reperfusion (CI/WR) liver injury remains a problem in liver transplants. Sinusoidal endothelial cells (SEC) are a target of CI/WR injury, during which they undergo apoptosis. Because Caspase proteases have been implicated in apoptosis, our aim was to determine whether liver CI/WR injury induces a Caspase-dependent apoptosis of SEC. Rat livers were stored in the University of Wisconsin (UW) solution for 24 hr at 4°C and reperfused for 1 hr at 37°C in vitro. Apoptosis was quantitated using the TUNEL assay, and Caspase 3 activation determined by immunohistochemical analysis. Rat liver orthotopic liver transplants (OLT) were also performed using livers stored for 30 hr. Terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) positive hepatocytes were rare and did not increase during CI/WR injury. In contrast, TUNEL positive SEC increased 6-fold after reperfusion of livers stored under cold ischemic conditions, compared with controls or livers stored but not reperfused. Immunohistochemical analysis demonstrated active Caspase 3 only in endothelial cells after CI/WR injury. When IDN-1965, a Caspase Inhibitor, was given i.v. to the donor animal and added to UW solution and the reperfusion media, TUNEL positive endothelial cells were reduced 63±11% (P<0.05). Similarly, the duration of survival after OLT was significantly increased in the presence of the Inhibitor. During liver CI/WR injury: 1) selective apoptosis of endothelial cells occurs; 2) Caspase 3 is activated only in endothelial cells; and 3) a Caspase Inhibitor reduces endothelial cell apoptosis and prolongs animal survival after OLT. The pharmacologic use of Caspase Inhibitors could prove useful in clinical transplantation.
Reinhard Gruber - One of the best experts on this subject based on the ideXlab platform.
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Caspase Inhibitor attenuates the shape changes in the alveolar ridge following tooth extraction a pilot study in rats
Journal of Periodontal Research, 2021Co-Authors: Uwe Yacine Schwarze, Franz Josef Strauss, Reinhard GruberAbstract:OBJECTIVE The aim of the study was to determine whether the inhibition of apoptosis via pan-Caspase Inhibitors can attenuate the changes in the alveolar ridge upon tooth extraction. BACKGROUND Cells undergoing apoptosis might play a central role in the onset of alveolar bone resorption and the ensuing bone atrophy following tooth extraction. Caspases are proteases that regulate apoptotic cell death. It is, therefore, reasonable to hypothesize that blocking apoptosis with pan-Caspase Inhibitors attenuates the changes in the alveolar ridge following tooth extraction. METHODS In 16 inbred rats, the mandibular first (M1) and second (M2) molars of one side were extracted. Following random allocation, the rats received either a cell-permeable pan-Caspase Inhibitor or diluent. After a healing period of 10 days, changes in shape and height of the alveolar ridge were examined using geometric morphometrics and linear measurements based on micro-computed tomography. RESULTS Geometric morphometric analysis revealed that the pan-Caspase Inhibitor prevented major shape changes of the alveolar ridge following M1 tooth extraction (P < .05). Furthermore, linear measurements confirmed that the pan-Caspase Inhibitor significantly prevented the atrophy of the alveolar ridge height following M1 tooth extraction compared to the diluent controls (-0.53 mm vs -0.24 mm; P = .012). M2 tooth extraction caused no shape changes of the alveolar ridge, and thus, the pan-Caspase Inhibitor group did not differ from the control group (-0.14 mm vs -0.05 mm; P = .931). CONCLUSIONS These findings suggest that the inhibition of apoptosis may attenuate shape changes of the alveolar ridge following M1 tooth extraction in rodents.
Niel C Hoglen - One of the best experts on this subject based on the ideXlab platform.
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a Caspase Inhibitor idn 6556 ameliorates early hepatic injury in an ex vivo rat model of warm and cold ischemia
Liver Transplantation, 2007Co-Authors: Niel C Hoglen, Dean M Anselmo, Masamichi Katori, Marian Kaldas, Xiuda Shen, Karen L Valentino, Charles Lassman, Ronald W Busuttil, Jerzy W Kupiecweglinski, Douglas G FarmerAbstract:This study examined the efficacy of the Caspase Inhibitor, IDN-6556, in a rat model of liver ischemia-reperfusion injury. Livers from male Sprague-Dawley rats were reperfused for 120 minutes after 24 hours of 4 degrees C cold storage in University of Wisconsin solution. Portal blood flow measurements estimated sinusoidal resistance, and bile production, alanine aminotransferase activities, and Suzuki scores were evaluated as parameters of hepatocyte/liver injury. Treated livers were exposed to 25 or 50 microM of IDN-6556 in University of Wisconsin storage solution and/or the perfusate. All treatment regimens with IDN-6556 significantly improved portal blood flow measured at 120 minutes, and significant improvements were seen as early as 30 minutes when Inhibitor was also present in the perfusate (P < 0.01). All treatment groups with IDN-6556 significantly increased bile production by 3-4-fold compared with controls (P < 0.01), and reductions in alanine aminotransferase activities were seen within 90 minutes of reperfusion (P < 0.05). These data were confirmed by improved Suzuki scores (less sinusoidal congestion, necrosis, and vacuolization) in all treated groups. Livers from the IDN-6556-treated groups had markedly reduced Caspase activities and TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-positive cells, suggesting reductions in apoptosis. IDN-6556 present in cold storage media ameliorated liver injury due to cold ischemia and reperfusion injury and may be a rational therapeutic approach to reduce the risk of liver ischemia in the clinical setting.
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characterization of idn 6556 3 2 2 tert butyl phenylaminooxalyl amino propionylamino 4 oxo 5 2 3 5 6 tetrafluoro phenoxy pentanoic acid a liver targeted Caspase Inhibitor
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Niel C Hoglen, Longshiuh Chen, Craig D Fisher, Brad P Hirakawa, Todd Groessl, Patricia C ContrerasAbstract:The potency, efficacy, and pharmacokinetic properties of IDN-6556 (3-[2-[(2-tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid), a first-in-class Caspase Inhibitor in clinical trials for the treatment of liver diseases, were characterized in vivo in rodent models. In the mouse alpha-Fas model of liver injury, i.p. administration of IDN-6556 resulted in marked reduction of alanine aminotransferase (ALT), apoptosis, and Caspase activities at a dose of 3 mg/kg. At this dose, IDN-6556 was also effective when given up to 2 h before alpha-Fas and as late as 4 h after alpha-Fas administration. In both the alpha-Fas and d-galactosamine/lipopolysaccharide (D-Gln/LPS) model, ED(50) values in the sub-milligram per kilogram range were established after a number of routes of administration (i.p., i.v., i.m., or p.o.), ranging from 0.04 to 0.38 mg/kg. Efficacy was also demonstrated in the rat D-Gln/LPS model with 67 and 72% reductions in ALT activities after i.p. and p.o. treatment with IDN-6556 (10 mg/kg), respectively. Pharmacokinetic analysis in the rat demonstrated rapid clearance after i.v., i.p., and s.c. administration with terminal t(1/2) ranging from 46 to 51 min. Low absolute bioavailability after p.o. administration was seen (2.7-4%), but portal drug concentrations after oral administration were 3-fold higher than systemic concentrations with a 3.7-fold increase in the terminal t(1/2), indicating a significant first-pass effect. Liver concentrations remained constant after oral administration for at least a 4-h period, reaching a C(max) of 2558 ng/g liver at 120 min. Last, 51 +/- 20 and 4.9 +/- 3.4% of IDN-6556 was excreted intact in bile after i.v. and p.o. administration, respectively. This evaluation indicates that IDN-6556 has marked efficacy in models of liver disease after oral administration and thus, is an excellent candidate for the treatment of liver diseases characterized by excessive apoptosis.