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Reiner Frey - One of the best experts on this subject based on the ideXlab platform.
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assessment of the effects of renal impairment on the pharmacokinetics of the soluble Guanylate Cyclase Activator cinaciguat after a single intravenous dose
The Journal of Clinical Pharmacology, 2012Co-Authors: John Lettieri, Reiner Frey, Christian Scheerans, Martin Blunck, Wolfgang Mück, Arthur L. Mazzu, Pavur R. SundaresanAbstract:This open-label, parallel-group, single-dose study assessed the safety and pharmacokinetics of cinaciguat, a novel soluble Guanylate Cyclase Activator in clinical development for the treatment of acute decompensated heart failure, in individuals with mild, moderate, or severe renal impairment compared with individuals with normal renal function. Cinaciguat was administered as a 100 µg/h continuous infusion over 4 hours. Plasma concentrations were determined by high-performance liquid chromatography coupled with mass spectrometry. Renal function had only minor effects on the pharmacokinetics of cinaciguat. The apparent volume of distribution at steady state was slightly increased in individuals with renal impairment. The total body clearance from plasma showed a slight tendency to increase with progression of renal impairment, which can be explained by an increased hematocrit in individuals with renal impairment. No relevant influence was found on the terminal half-life. The fraction of cinaciguat unbound in plasma was very low (<1%) in all groups. Pharmacokinetic variability tended to be somewhat increased in individuals with renal impairment. Adverse events were mostly mild, and their incidence was similar in all groups. In conclusion, cinaciguat, a promising drug candidate for the treatment of acute decompensated heart failure, will not require dose adjustment based on renal function.
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Pharmacokinetics of the soluble Guanylate Cyclase Activator cinaciguat in individuals with hepatic impairment.
The Journal of Clinical Pharmacology, 2012Co-Authors: Reiner Frey, Christian Scheerans, Martin Blunck, Wolfgang Mück, Mark Jean Gnoth, Sigrun Unger, Anja Schmidt, Georg WensingAbstract:Cinaciguat is intended for use in patients with acute decompensated heart failure. The drug is eliminated predominantly via the liver and, therefore, the potential impact of hepatic impairment on cinaciguat pharmacokinetics needs to be determined. This nonrandomized, open-label, observational study investigated the pharmacokinetics of cinaciguat in individuals with mild (Child-Pugh A; n = 8) or moderate (Child-Pugh B; n = 8) hepatic impairment and matched healthy volunteers (n = 16). An exploratory analysis of pharmacodynamic parameters was also conducted. Individuals with mild hepatic impairment and their controls received a single (4-hour) intravenous infusion of 100 µg/h cinaciguat, whereas individuals with moderate hepatic impairment and their controls received 50 µg/h. Cinaciguat was well tolerated and had a favorable safety profile. The most frequent treatment-emergent adverse events were headache (4 participants) and spontaneous penile erection (2 participants). In individuals with mild hepatic impairment, only minor increases in plasma cinaciguat concentrations and no significant differences in pharmacodynamic parameters were observed, compared with controls. Individuals with moderate hepatic impairment had a substantially higher cinaciguat exposure than controls. This higher exposure was associated with more pronounced vasodilatation. This study demonstrates that in individuals with mild hepatic impairment, individual dose adaptation may not be required.
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Assessment of the Effects of Renal Impairment on the Pharmacokinetics of the Soluble Guanylate Cyclase Activator Cinaciguat After a Single Intravenous Dose
The Journal of Clinical Pharmacology, 2012Co-Authors: John Lettieri, Reiner Frey, Christian Scheerans, Martin Blunck, Wolfgang Mück, Arthur L. Mazzu, Pavur R. SundaresanAbstract:This open-label, parallel-group, single-dose study assessed the safety and pharmacokinetics of cinaciguat, a novel soluble Guanylate Cyclase Activator in clinical development for the treatment of acute decompensated heart failure, in individuals with mild, moderate, or severe renal impairment compared with individuals with normal renal function. Cinaciguat was administered as a 100 µg/h continuous infusion over 4 hours. Plasma concentrations were determined by high-performance liquid chromatography coupled with mass spectrometry. Renal function had only minor effects on the pharmacokinetics of cinaciguat. The apparent volume of distribution at steady state was slightly increased in individuals with renal impairment. The total body clearance from plasma showed a slight tendency to increase with progression of renal impairment, which can be explained by an increased hematocrit in individuals with renal impairment. No relevant influence was found on the terminal half-life. The fraction of cinaciguat unbound in plasma was very low (
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antiplatelet effects of aspirin are not affected by the soluble Guanylate Cyclase Activator cinaciguat bay 58 2667
BMC Pharmacology, 2011Co-Authors: Reiner Frey, Wolfgang Mueck, Michael Becka, Joern Kraetzschmar, Georg WensingAbstract:IntroductionCinaciguat (BAY 58-2667) is an nitric oxide (NO)-inde-pendent and heme-independent soluble GuanylateCyclase (sGC) Activator. Cinaciguat preferentially acti-vates sGC in its oxidized or heme-free state, when theenzyme is insensitive to its endogenous ligand NO andexogenous nitrovasodilators [1].Endothelium-derived NO is one of the mechanisms bywhich platelet aggregation and thrombus formation isprevented by the intact blood vessel wall. Pharmacologi-cal stimulation of sGC in platelets correlates with inhibi-tion of aggregation, platelet cGMP increase, prolongationof bleeding time and antithrombotic effects in vitro [2].This protective mechanism may be impaired in vasculardisease and impaired NO availability. Thus, sGC activa-tors may have antithrombotic effects similar to endogen-ous NO. Indeed, cinaciguat potently inhibited plateletaggregation induced by the thromboxane mimic U46619and collagen and prolonged rat-tail bleeding time up to2-fold [3]. Thus, in vitro data suggested that coadminis-tration of cinaciguat and aspirin may increase the antipla-telet effects of aspirin and could result in bleeding.MethodsThis non-randomized, open-label trial was conductedfrom September to November 2001 in a single center inGermany. It was carried out in accordance with theDeclaration of Helsinki and adhered to the InternationalConference of Harmonization good clinical practiceguidelines and the German drug law (AMG). The studyprotocol was approved by the Ethics Committee of theNorth-Rhine Medical Council, Duesseldorf, Germany.The study consisted of a 9-day treatment phase with100 mg oral acetylsalicylicacid (aspirin) once dailyadministered in the morning in the fasting state and,after the last dose of aspirin, four sequential oral dosesof 1.5 mg cinaciguat administered in the fasting state at1-hour intervals. The first dose of cinaciguat was admi-nistered together with the last dose of aspirin. This cina-ciguat dosing schedule was used to mimic a prolongedplasma concentration over time profile.Results12 healthy men (mean age, 32.4 years, range, 23 - 42years) were enrolled and completed the study accordingto protocol.Low-dose aspirin treatment in healthy subjectsresulted in the expected inhibition of platelet aggrega-tion. 4 oral doses of 1.5 mg cinaciguat administered at1-hour intervals did not significantly affect plateletaggregation induced by collagen and the thromboxaneA2 mimetic U 46619 or bleeding time. These results arein line with the findings of a single dose escalationstudy.Plasma pharmacokinetics of cinaciguat following 4oral doses of 1.5 mg cinaciguat administered at 1-hourintervals showed pronounced inter-individual variability.There was no major pharmacokinetic interactiondetected between aspirin and cinaciguat, compared withthe data of a previous study, which applied the samedosing regimen.ConclusionCoadministration of cinaciguat and aspirin did notreveal any pharmacodynamic interaction with respect of
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pharmacokinetic analysis of the soluble Guanylate Cyclase Activator cinaciguat bay 58 2667 in individuals with renal impairment compared to healthy controls
BMC Pharmacology, 2011Co-Authors: Christian Scheerans, Martin Blunck, Wolfgang Mueck, Reiner FreyAbstract:Background Cinaciquat (CIN) is a Guanylate Cyclase (sGC) Activator that induces cyclic GMP generation and vasodilation preferentially in diseased vessels [1]. CIN has the potential to increase cardiac output in patients with acute decompensated heart failure [2]. CIN is predominantly and rapidly cleared by the liver [3], and thus, it was not expected that the kidney function would have an influence on CIN clearance. Nevertheless, we determined the pharmacokinetics of CIN in individuals with renal impairment and ageand gender-matched healthy volunteers with normal renal function [4].
Shengchu Kuo - One of the best experts on this subject based on the ideXlab platform.
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enhancement of learning behaviour by a potent nitric oxide Guanylate Cyclase Activator yc 1
European Journal of Neuroscience, 2005Co-Authors: Weilin Chien, Shengchu Kuo, K C Liang, Cheming Teng, Fangyu LeeAbstract:Memory is one of the most fundamental mental processes, and various approaches have been used to understand the mechanisms underlying this process. Nitric oxide (NO), cGMP and protein kinase G (PKG) are involved in the modulation of synaptic plasticity in various brain regions. YC-1, which is a benzylindazole derivative, greatly potentiated the response of soluble Guanylate Cyclase to NO (up to several hundreds fold). We have previously shown that YC-1 markedly enhances long-term potentiation in hippocampal and amygdala slices via NO-cGMP-PKG-dependent pathway. We here further investigated whether YC-1 promotes learning behaviour in Morris water maze and avoidance tests. It was found that YC-1 shortened the escape latency in the task of water maze, increased and decreased the retention scores in passive and active avoidance task, respectively. Administration of YC-1 30 min after foot-shock stimulation did not significantly affect retention scores in response to passive avoidance test. Administration of scopolamine, a muscarinic antagonist, markedly impaired the memory acquisition. Pretreatment of YC-1 inhibited the scopolamine-induced learning deficit. The enhancement of learning behaviour by YC-1 was antagonized by intracerebroventricular injection of NOS inhibitor L-NAME and PKG inhibitors of KT5823 and Rp-8-Br-PET-cGMPS, indicating that NO-cGMP-PKG pathway is also involved in the learning enhancement action of YC-1. YC-1 is thus a good drug candidate for the improvement of learning and memory.
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vasorelaxant effect of isoliquiritigenin a novel soluble Guanylate Cyclase Activator in rat aorta
British Journal of Pharmacology, 1995Co-Authors: Shengchu KuoAbstract:1. The vasorelaxant activity of isoliquiritigenin, isolated from Dalbergia odorifera T, was investigated in the phenylephrine-precontracted rat aorta by measuring tension, Guanylate and adenylate Cyclase activities, guanosine 3':5'-cyclic monophosphate (cyclic GMP) and adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. 2. Isoliquiritigenin concentration-dependently relaxed rat aorta contracted with phenylephrine, KCl, U-46619, endothelin and 5-hydroxytryptamine, with EC50s of 7.4 +/- 1.6, 10.5 +/- 2.3, 14.3 +/- 3.3, 11.8 +/- 2.0 and 13.6 +/- 3.7 microM, respectively. 3. Isoliquiritigenin caused endothelium-independent relaxation of phenylephrine-precontracted rat aortic rings. Neither NG-monomethyl-L-arginine (L-NMMA) (an inhibitor of the L-arginine-NO pathway) nor oxyhaemoglobin (which binds NO) modified the relaxant effect of isoliquiritigenin. The relaxant action of isoliquiritigenin also persisted in intact aorta in the presence of indomethacin or glibenclamide. However, methylene blue, an inhibitor of soluble Guanylate Cyclase, abolished relaxation induced by isoliquiritigenin. 4. Incubation of rat aorta with isoliquiritigenin not only increased aortic cyclic GMP content but also caused small increases in aortic cyclic AMP content, and greatly potentiated the increases in cyclic AMP observed in the presence of forskolin. The maximum increase in cyclic GMP by isoliquiritigenin was reached earlier than the increase in cyclic AMP. This result suggests that the increases in cyclic GMP caused by isoliquiritigenin might stimulate the accumulation of cyclic AMP. 5. Concentration-dependent increases in soluble Guanylate Cyclase activity were observed in isoliquiritigenin (1-100 microM)- or sodium nitroprusside (SNP)-treated rat aortic smooth muscle cells, while adenylate Cyclase activity was unchanged in isoliquiritigenin (100 microM)-treated cells. 6. Relaxation and cyclic AMP formation of rat aorta caused by isoliquiritigenin was potentiated in the presence of forskolin (10 nM), which had little effect when given alone. 2',5'-Dideoxyadenosine (DDA,200 microM), an adenylate Cyclase inhibitor, diminished the relaxation and cyclic AMP formation of rat aorta by isoliquiritigenin only in the presence of forskolin. DDA did not affect the increases in cyclic GMP formation induced by isoliquiritigenin. These results suggest that elevated levels of cyclic GMP may mediate the majority of the relaxation of the phenylephrine-precontracted aorta induced byisoliquiritigenin, while the synergistic interaction with a low concentration of forskolin depends on an enhanced accumulation of cyclic AMP.7. Relaxation of phenylephrine-precontracted rat aorta and carbachol-precontracted guinea-pig trachea by rolipram (phosphodiesterase, PDE IV inhibitor) was markedly enhanced by isoliquiritigenin, while response to cilostamide (PDE III inhibitor) was not significantly changed by isoliquiritigenin.8. It is concluded that isoliquiritigenin exerts a vasorelaxant effect by activating soluble GuanylateCyclase and increasing cyclic GMP. Synergistic effects of isoliquiritigenin and forskolin on muscle relaxation and cyclic AMP accumulation indicate that inhibition of cyclic AMP breakdown by cyclic GMP via the inhibition of PDE III (cyclic GMP-inhibited PDE) is the dominant mechanism.
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yc 1 a novel Activator of platelet Guanylate Cyclase
Blood, 1994Co-Authors: Shengchu Kuo, Fangyu Lee, Cheming TengAbstract:YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole] inhibited the aggregation of and ATP release from washed rabbit platelets induced by arachidonic acid (AA), collagen, U46619, platelet-activating factor (PAF), and thrombin in a concentration-dependent manner. YC-1 also disaggregated the clumped platelets caused by these inducers. The thromboxane B2 formation caused by collagen, PAF, and thrombin was inhibited by concentrations of YC-1 that did not affect formation of thromboxane B2 and prostaglandin D2 caused by AA. YC-1 suppressed the increase of intracellular Ca2+ concentration and generation of inositol 1,4,5-trisphosphate caused by these five aggregation inducers. Both the cAMP and cGMP contents of platelets were increased by YC-1 in a concentration- and time-dependent manner. Like sodium nitroprusside, YC-1 potentiated formation of cAMP caused by prostaglandin E1 but not that by 3-isobutyl-1-methylxanthine. Adenylate Cyclase and cAMP phosphodiesterase activities were not altered by YC-1. Activity of cGMP phosphodiesterase was unaffected by YC-1. Activities of Guanylate Cyclase in platelet homogenate and cytosolic fraction were activated by YC-1, whereas particulate Guanylate Cyclase activity was unaffected. The antiplatelet effect of sodium nitroprusside but not that of YC-1 was blocked by hemoglobin and potentiated by superoxide dismutase. After intraperitoneal administration for 30 minutes, YC-1 prolonged the tail bleeding time of conscious mice. These data indicate that YC-1 is a direct soluble Guanylate Cyclase Activator in rabbit platelets. It may also possess antithrombotic potential in vivo.
Takeru Ehara - One of the best experts on this subject based on the ideXlab platform.
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a novel selective soluble Guanylate Cyclase Activator mgv354 lowers intraocular pressure in preclinical models following topical ocular dosing
Investigative Ophthalmology & Visual Science, 2018Co-Authors: Ganesh Prasanna, Luciana Ferrara, Christopher M Adams, Takeru Ehara, Louis Yang, Chuanxi Xiang, Sean Kim, Christopher Towler, Todd Topley, Cale McallisterAbstract:Purpose The nitric oxide/soluble Guanylate Cyclase/protein kinase G (NO/sGC/PKG) is known to be involved in the regulation of intraocular pressure (IOP) and may be dysregulated in glaucoma. The purpose is to demonstrate that the sGC Activator MGV354 lowers IOP in a monkey model of glaucoma and could be considered as a possible new clinical drug candidate. Methods Changes to cGMP were assessed in primary human trabecular meshwork (hNTM) cells and binding studies were conducted using human sGC full-length protein. Ocular safety tolerability, exposure, and efficacy studies were conducted in rabbit and monkey models following topical ocular dosing of MGV354. Results sGC was highly expressed in the human and cynomolgus monkey outflow pathways. MGV354 had a 7-fold greater Bmax to oxidized sGC compared to that of reduced sGC and generated an 8- to 10-fold greater cGMP compared to that of a reduced condition in hTM cells. A single topical ocular dose with MGV354 caused a significant dose-dependent reduction of 20% to 40% (versus vehicle), lasting up to 6 hours in pigmented rabbits and 24 hours postdose in a cynomolgus monkey model of glaucoma. The MGV354-induced IOP lowering was sustained up to 7 days following once-daily dosing in a monkey model of glaucoma and was greater in magnitude compared to Travatan (travoprost)-induced IOP reduction. Mild to moderate ocular hyperemia was the main adverse effect noted. Conclusions MGV354 represents a novel class of sGC Activators that can lower IOP in preclinical models of glaucoma. The potential for sGC Activators to be used as effective IOP-lowering drugs in glaucoma patients could be further determined in clinical studies.
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the discovery of s 1 6 3 4 1 cyclopropanecarbonyl piperidin 4 yl 2 methylphenyl amino 2 3 dihydro 1h inden 4 yl pyridin 2 yl 5 methyl 1h pyrazole 4 carboxylic acid a soluble Guanylate Cyclase Activator specifically designed for topical ocular deliver
Journal of Medicinal Chemistry, 2018Co-Authors: Takeru Ehara, Christopher M Adams, Doug Bevan, Erik Meredith, David B Belanger, James J Powers, Mitsunori Kato, Catherine Solovay, Donglei Liu, Michael Paul CapparelliAbstract:Soluble Guanylate Cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases associated with oxidative stress. In a pathological oxidative environment, the heme group of sGC can be oxidized becoming unresponsive to NO leading to a loss in the ability to catalyze the production of cGMP. Recently a dysfunctional sGC/NO/cGMP pathway has been implicated in contributing to elevated intraocular pressure associated with glaucoma. Herein we describe the discovery of molecules specifically designed for topical ocular administration, which can activate oxidized sGC restoring the ability to catalyze the production of cGMP. These efforts culminated in the identification of compound (+)-23, which robustly lowers intraocular pressure in a cynomolgus model of elevated intraocular pressure over 24 h after a single topical ocular drop and has been selected for clinical evaluation.
Pavur R. Sundaresan - One of the best experts on this subject based on the ideXlab platform.
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assessment of the effects of renal impairment on the pharmacokinetics of the soluble Guanylate Cyclase Activator cinaciguat after a single intravenous dose
The Journal of Clinical Pharmacology, 2012Co-Authors: John Lettieri, Reiner Frey, Christian Scheerans, Martin Blunck, Wolfgang Mück, Arthur L. Mazzu, Pavur R. SundaresanAbstract:This open-label, parallel-group, single-dose study assessed the safety and pharmacokinetics of cinaciguat, a novel soluble Guanylate Cyclase Activator in clinical development for the treatment of acute decompensated heart failure, in individuals with mild, moderate, or severe renal impairment compared with individuals with normal renal function. Cinaciguat was administered as a 100 µg/h continuous infusion over 4 hours. Plasma concentrations were determined by high-performance liquid chromatography coupled with mass spectrometry. Renal function had only minor effects on the pharmacokinetics of cinaciguat. The apparent volume of distribution at steady state was slightly increased in individuals with renal impairment. The total body clearance from plasma showed a slight tendency to increase with progression of renal impairment, which can be explained by an increased hematocrit in individuals with renal impairment. No relevant influence was found on the terminal half-life. The fraction of cinaciguat unbound in plasma was very low (<1%) in all groups. Pharmacokinetic variability tended to be somewhat increased in individuals with renal impairment. Adverse events were mostly mild, and their incidence was similar in all groups. In conclusion, cinaciguat, a promising drug candidate for the treatment of acute decompensated heart failure, will not require dose adjustment based on renal function.
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Assessment of the Effects of Renal Impairment on the Pharmacokinetics of the Soluble Guanylate Cyclase Activator Cinaciguat After a Single Intravenous Dose
The Journal of Clinical Pharmacology, 2012Co-Authors: John Lettieri, Reiner Frey, Christian Scheerans, Martin Blunck, Wolfgang Mück, Arthur L. Mazzu, Pavur R. SundaresanAbstract:This open-label, parallel-group, single-dose study assessed the safety and pharmacokinetics of cinaciguat, a novel soluble Guanylate Cyclase Activator in clinical development for the treatment of acute decompensated heart failure, in individuals with mild, moderate, or severe renal impairment compared with individuals with normal renal function. Cinaciguat was administered as a 100 µg/h continuous infusion over 4 hours. Plasma concentrations were determined by high-performance liquid chromatography coupled with mass spectrometry. Renal function had only minor effects on the pharmacokinetics of cinaciguat. The apparent volume of distribution at steady state was slightly increased in individuals with renal impairment. The total body clearance from plasma showed a slight tendency to increase with progression of renal impairment, which can be explained by an increased hematocrit in individuals with renal impairment. No relevant influence was found on the terminal half-life. The fraction of cinaciguat unbound in plasma was very low (
Cheming Teng - One of the best experts on this subject based on the ideXlab platform.
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enhancement of learning behaviour by a potent nitric oxide Guanylate Cyclase Activator yc 1
European Journal of Neuroscience, 2005Co-Authors: Weilin Chien, Shengchu Kuo, K C Liang, Cheming Teng, Fangyu LeeAbstract:Memory is one of the most fundamental mental processes, and various approaches have been used to understand the mechanisms underlying this process. Nitric oxide (NO), cGMP and protein kinase G (PKG) are involved in the modulation of synaptic plasticity in various brain regions. YC-1, which is a benzylindazole derivative, greatly potentiated the response of soluble Guanylate Cyclase to NO (up to several hundreds fold). We have previously shown that YC-1 markedly enhances long-term potentiation in hippocampal and amygdala slices via NO-cGMP-PKG-dependent pathway. We here further investigated whether YC-1 promotes learning behaviour in Morris water maze and avoidance tests. It was found that YC-1 shortened the escape latency in the task of water maze, increased and decreased the retention scores in passive and active avoidance task, respectively. Administration of YC-1 30 min after foot-shock stimulation did not significantly affect retention scores in response to passive avoidance test. Administration of scopolamine, a muscarinic antagonist, markedly impaired the memory acquisition. Pretreatment of YC-1 inhibited the scopolamine-induced learning deficit. The enhancement of learning behaviour by YC-1 was antagonized by intracerebroventricular injection of NOS inhibitor L-NAME and PKG inhibitors of KT5823 and Rp-8-Br-PET-cGMPS, indicating that NO-cGMP-PKG pathway is also involved in the learning enhancement action of YC-1. YC-1 is thus a good drug candidate for the improvement of learning and memory.
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yc 1 a novel Activator of platelet Guanylate Cyclase
Blood, 1994Co-Authors: Shengchu Kuo, Fangyu Lee, Cheming TengAbstract:YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole] inhibited the aggregation of and ATP release from washed rabbit platelets induced by arachidonic acid (AA), collagen, U46619, platelet-activating factor (PAF), and thrombin in a concentration-dependent manner. YC-1 also disaggregated the clumped platelets caused by these inducers. The thromboxane B2 formation caused by collagen, PAF, and thrombin was inhibited by concentrations of YC-1 that did not affect formation of thromboxane B2 and prostaglandin D2 caused by AA. YC-1 suppressed the increase of intracellular Ca2+ concentration and generation of inositol 1,4,5-trisphosphate caused by these five aggregation inducers. Both the cAMP and cGMP contents of platelets were increased by YC-1 in a concentration- and time-dependent manner. Like sodium nitroprusside, YC-1 potentiated formation of cAMP caused by prostaglandin E1 but not that by 3-isobutyl-1-methylxanthine. Adenylate Cyclase and cAMP phosphodiesterase activities were not altered by YC-1. Activity of cGMP phosphodiesterase was unaffected by YC-1. Activities of Guanylate Cyclase in platelet homogenate and cytosolic fraction were activated by YC-1, whereas particulate Guanylate Cyclase activity was unaffected. The antiplatelet effect of sodium nitroprusside but not that of YC-1 was blocked by hemoglobin and potentiated by superoxide dismutase. After intraperitoneal administration for 30 minutes, YC-1 prolonged the tail bleeding time of conscious mice. These data indicate that YC-1 is a direct soluble Guanylate Cyclase Activator in rabbit platelets. It may also possess antithrombotic potential in vivo.