Safety and Efficacy of Fasudil Monotherapy and Fasudil-Ozagrel Combination Therapy in Patients With Subarachnoid Hemorrhage: Sub-analysis of the Post-marketing Surveillance Study

Suzuki, Yoshio; Shibuya, Masabumi; Satoh, Shin’ichi; Sugiyama, Hirotoshi; Seto, Minoru; Takakura, Kintomo

doi:10.2176/nmc.48.241

Cited by 66 publications

(48 citation statements)

References 23 publications

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“…23,42 Interestingly, both our data and 1 of the earlier reports in CML suggest that normal HSPCs are less sensitive to ROCK1 inhibition than leukemic blasts. These observations and the excellent tolerability of prolonged fasudil exposure in humans 43,44 and in our mouse model argue for the feasibility of repetitive dosing to increase peak serum levels observed after a single application of this drug 25 to levels needed for efficient ROCK1 inhibition in vivo. The absence of any signs of hematotoxicity in clinical trials on fasudil is further arguing in favor of this proposition.…”

Section: Discussionmentioning

confidence: 64%

RNAi profiling of primary human AML cells identifies ROCK1 as a therapeutic target and nominates fasudil as an antileukemic drug

Wermke

Camgöz

Paszkowski‐Rogacz

et al. 2015

Blood

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Key Points• Large-scale loss-of-function RNAi screens in patientderived AML cells are feasible and able to pinpoint therapeutic targets.• ROCK1 inhibition exerts antileukemic effects in primary human AML cells in vitro and in vivo.Acute myeloid leukemia (AML) is characterized by a marked genetic heterogeneity, which complicates the development of novel therapeutics. The delineation of pathways essential within an individual patient's mutational background might overcome this limitation and facilitate personalized treatment. We report the results of a large-scale lentiviral lossof-function RNA interference (RNAi) screen in primary leukemic cells. Stringent validation identified 6 genes (BNIPL1, ROCK1, RPS13, STK3, SNX27, WDHD1) whose knockdown impaired growth and viability of the cells. Dependence on these genes was not caused by mutation or overexpression, and although some of the candidates seemed to be rather patient specific, others were essential in cells isolated from other AML patients. In addition to the phenotype observed after ROCK1 knockdown, treatment with the approved ROCK inhibitor fasudil resulted in increased apoptosis and decreased viability of primary AML cells. In contrast to observations in some other malignancies, ROCK1 inhibition did not foster growth of immature malignant progenitors but was toxic to this cell fraction in feeder coculture and xenotransplant experiments, indicating a distinct effect of ROCK1 inhibition on leukemic progenitors. We conclude that large-scale RNAi screens in primary patient-derived cells are feasible and can complement other methods for personalized cancer therapies, such as expression and mutation profiling. (Blood. 2015;125(24):3760-3768)

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Section: Discussionmentioning

confidence: 64%

RNAi profiling of primary human AML cells identifies ROCK1 as a therapeutic target and nominates fasudil as an antileukemic drug

Wermke

Camgöz

Paszkowski‐Rogacz

et al. 2015

Blood

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“…The inhibition of ROCK with the ROCK-inhibitor Y-27632 had no obvious adverse effects in mice. Administration of the ROCK-inhibitor fasudil to humans with subarachnoid hemorrhage was well tolerated (Suzuki et al, 2007(Suzuki et al, , 2008, indicating that treatment of humans with ROCK-inhibitors might be feasible.…”

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confidence: 99%

Myosin IXa Regulates Epithelial Differentiation and Its Deficiency Results in Hydrocephalus

Abouhamed

Grobe

San

et al. 2009

MBoC

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The ependymal multiciliated epithelium in the brain restricts the cerebrospinal fluid to the cerebral ventricles and regulates its flow. We report here that mice deficient for myosin IXa (Myo9a), an actin-dependent motor molecule with a Rho GTPase-activating (GAP) domain, develop severe hydrocephalus with stenosis and closure of the ventral caudal 3rd ventricle and the aqueduct. Myo9a is expressed in maturing ependymal epithelial cells, and its absence leads to impaired maturation of ependymal cells. The Myo9a deficiency further resulted in a distorted ependyma due to irregular epithelial cell morphology and altered organization of intercellular junctions. Ependymal cells occasionally delaminated, forming multilayered structures that bridged the CSF-filled ventricular space. Hydrocephalus formation could be significantly attenuated by the inhibition of the Rho-effector Rho-kinase (ROCK). Administration of ROCK-inhibitor restored maturation of ependymal cells, but not the morphological distortions of the ependyma. Similarly, down-regulation of Myo9a by siRNA in Caco-2 adenocarcinoma cells increased Rho-signaling and induced alterations in differentiation, cell morphology, junction assembly, junctional signaling, and gene expression. Our results demonstrate that Myo9a is a critical regulator of Rho-dependent and -independent signaling mechanisms that guide epithelial differentiation. Moreover, Rho-kinases may represent a new target for therapeutic intervention in some forms of hydrocephalus. INTRODUCTIONThe development and homeostasis of multicellular organisms depends on coordinated cell shape changes that are coupled with alterations in intracellular organization. The dynamic organization of the actin cytoskeleton accounts for many cell shape changes. A multitude of proteins can directly or indirectly modify the dynamics and organization of the actin cytoskeleton. Among these proteins are monomeric GTPases and the superfamily of myosin molecules. The myosin superfamily of actin-based molecular motors is subdivided into more than 30 classes (Odronitz and Kollmar, 2007). The class IX of myosin molecules includes in mammals two members, Myo9a (myr 7) and Myo9b (myr 5), that are both expressed in a number of differentially spliced variants (Bähler, 2008). The Myo9a protein, previously also called myr 7, is expressed during development and in many adult tissues, most abundantly in brain and testis (Chieregatti et al., 1998;Gorman et al., 1999). Class IX myosins comprise in addition to their myosin head domain a tail region that encompasses a C1 domain and a Rho GTPaseactivating protein (RhoGAP) domain (Reinhard et al., 1995;Chieregatti et al., 1998). The RhoGAP domain negatively regulates the monomeric Rho GTPase by accelerating its rate of GTP-hydrolysis, switching it from the active GTP-bound form to the inactive GDP-bound form. The RhoGTPases are known to be important regulators of cell morphogenesis, cell migration, and cell proliferation (Jaffe and Hall, 2005). They are inactivated under spatial and temporal con...

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“…Hydroxyfasudil improves hemodynamic function by increasing regional cerebral blood flow and ameliorating endothelial damage/dysfunction, and it prevents the inflammatory response by inhibiting neutrophil and monocyte infiltration (14 -17). The area under the plasma concentration-time curve value of hydroxyfasudil was approximately 4.5 times higher than that of fasudil in patients with SAH receiving 30 mg of fasudil (18).…”

Section: Introductionmentioning

confidence: 77%

“…Hydroxyfasudil was found following intravenous infusion of fasudil (30 mg/30 min) in patients with SAH (18). The elimination half-life of hydroxyfasudil is longer than that of fasudil, and the AUC value of hydroxyfasudil is approximately 4.5 times higher than that of fasudil.…”

Section: Discussionmentioning

confidence: 95%

Antivasospastic Effects of Hydroxyfasudil, a Rho-Kinase Inhibitor, After Subarachnoid Hemorrhage

et al. 2012

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Abstract. We investigated the anti-vasospastic potential of fasudil's active metabolite, hydroxyfasudil, a Rho-kinase inhibitor, after subarachnoid hemorrhage (SAH) and also its effect on hemorheological abnormalities following cerebral ischemia. Chronic cerebral vasospasm was produced using a two-hemorrhage canine model. On day 7, angiographic vasospasm was observed in all animals, and intravenous administration of hydroxyfasudil (3 mg·kg) significantly reversed the vasospasm (predose diameter of the basilar artery, 57.9% ± 2.0% of the baseline before the injection of blood; postdose diameter, 64.5% ± 1.9%). The viscosity of whole blood was significantly increased 24 h after 1 h middle cerebral artery occlusion in rats. Hydroxyfasudil (3 and 10 mg/kg, i.p.) significantly decreased blood viscosity. The specificity of hydroxyfasudil was examined against a panel of 17 protein kinases using ELISA analysis. Hydroxyfasudil inhibited Rho-kinase α and β at a concentration of 10 μM by 97.6% and 97.7%, respectively. No other protein kinase was inhibited with 10 μM hydroxyfasudil by over 40%. The present results indicate hydroxyfasudil is a selective inhibitor of Rho-kinase. The results also suggest that hydroxyfasudil contributes to the potency of fasudil to prevent cerebral vasospasm and hyperviscosity and suggest the potential utility of hydroxyfasudil as a therapeutic agent for patients with SAH.

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Safety and Efficacy of Fasudil Monotherapy and Fasudil-Ozagrel Combination Therapy in Patients With Subarachnoid Hemorrhage: Sub-analysis of the Post-marketing Surveillance Study

Cited by 66 publications

References 23 publications

RNAi profiling of primary human AML cells identifies ROCK1 as a therapeutic target and nominates fasudil as an antileukemic drug

RNAi profiling of primary human AML cells identifies ROCK1 as a therapeutic target and nominates fasudil as an antileukemic drug

Myosin IXa Regulates Epithelial Differentiation and Its Deficiency Results in Hydrocephalus

Antivasospastic Effects of Hydroxyfasudil, a Rho-Kinase Inhibitor, After Subarachnoid Hemorrhage

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