The Experts below are selected from a list of 7149 Experts worldwide ranked by ideXlab platform
Hiroaki Shimokawa - One of the best experts on this subject based on the ideXlab platform.
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acute vasodilator effects of inhaled fasudil a specific Rho Kinase Inhibitor in patients with pulmonary arterial hypertension
Heart and Vessels, 2010Co-Authors: Hiroshi Fujita, Yoshihiro Fukumoto, Kenya Saji, Koichiro Sugimura, Jun Demachi, Jun Nawata, Hiroaki ShimokawaAbstract:We have previously demonstrated that long-term inhibition of Rho-Kinase ameliorates pulmonary arterial hypertension (PAH) in animal models. In the present study, we examined acute vasodilator effects of inhaled fasudil, a specific Rho-Kinase Inhibitor, as a more feasible option to locally deliver the drug for PAH. We examined 15 patients with PAH (13 women and 2 men, 45 ± 4 years old), including idiopathic PAH (n = 5), PAH associated with connective tissue disease (n = 6), PAH with congenital heart disease (n = 3), and portal PAH (n = 1). In those patients, we performed right heart catheterization with a Swan-Ganz catheter in the two protocols with inhalation of nitric oxide (NO) (40 ppm, 10 min) and fasudil (30 mg, 10 min) with a sufficient interval (>30 min). Both NO and fasudil inhalation significantly reduced mean pulmonary arterial pressure (PAP) (NO: P < 0.01, fasudil: P < 0.05) and tended to decrease pulmonary vascular resistance (NO: P = 0.07, fasudil: P = 0.1), but did not affect cardiac index. The ratio of pulmonary to systemic vascular resistance was significantly reduced both in NO and fasudil inhalation (NO: P < 0.01, fasudil: P < 0.05), indicating that both NO and fasudil inhalation selectively affect lung tissues. Interestingly, there was no correlation in the vasodilator effects between NO and fasudil, and a positive correlation with serum levels of high-sensitivity C-reactive protein was noted for fasudil but not for NO. These results suggest that inhalation of fasudil is as effective as NO in patients with PAH, possibly through different mechanisms.
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acute vasodilator effect of fasudil a Rho Kinase Inhibitor in monocrotaline induced pulmonary hypertension in rats
Journal of Cardiovascular Pharmacology, 2007Co-Authors: Bao Hua Jiang, Hiroaki Shimokawa, Shunsuke Tawara, Yoshihiro Fukumoto, Kohtaro Abe, Aya TakakiAbstract:Pulmonary arterial hypertension is a progressive and fatal disease for which Rho-Kinase may be substantially involved. In this study, we examined the acute vasodilator effects of fasudil, a Rho-Kinase Inhibitor, in monocrotaline (MCT)-induced pulmonary hypertension (PH) in rats. Three weeks after a single subcutaneous injection of MCT (60 mg/kg), hemodynamic variables were measured under conscious and free-moving conditions before and after oral administration of fasudil. MCT caused a significant elevation of mean pulmonary arterial pressure (mPAP). Although a low dose of fasudil (3 mg/kg) had no effect on mPAP, a middle dose (10 mg/kg) caused a significant reduction in mPAP without change in mean systemic arterial pressure (mSAP), and a high dose (30 mg/kg) significantly reduced both mPAP and mSAP. Rho-Kinase activity was significantly increased by MCT injection in pulmonary arteries but not in the aorta. Fasudil (10 mg/kg) inhibited only the Rho-Kinase activity in pulmonary arteries without any effect in the aorta. Plasma concentration of hydroxyfasudil, a metabolite of fasudil, was within its clinical range in humans. These results demonstrate that fasudil exerts effective and selective vasodilatation of pulmonary arteries in rats with MCT-induced PH at a given dose, suggesting its usefulness for the treatment of the fatal disorder.
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Effects of combined therapy with a Rho-Kinase Inhibitor and prostacyclin on monocrotaline-induced pulmonary hypertension in rats.
Journal of cardiovascular pharmacology, 2007Co-Authors: Shunsuke Tawara, Yoshihiro Fukumoto, Hiroaki ShimokawaAbstract:Pulmonary hypertension (PH) is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells, and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have previously demonstrated that long-term inhibition of Rho-Kinase, an effector of the small GTPase Rho, ameliorates monocrotaline-induced PH in rats and hypoxia-induced PH in mice. We also have reported that prostacyclin and its oral analogue, beraprost sodium (BPS), may lack direct Inhibitory effect on Rho-Kinase in vitro, suggesting that combination therapy with a Rho-Kinase Inhibitor and BPS is effective for the treatment of PH. In this study, we addressed this point in monocrotaline-induced PH model in rats. Male Sprague-Dawley rats were given a subcutaneous injection of monocrotaline (60 mg/kg). They were maintained with or without the treatment with a Rho-Kinase Inhibitor, fasudil (30 mg/kg/day), BPS (200 microg/kg/day), or a combination of both drugs for 3 weeks. The combination therapy, when compared with each monotherapy, showed significantly more improvement in PH, right ventricular hypertrophy, and pulmonary medial thickness without any adverse effects. Plasma concentrations of fasudil were not affected by BPS. These results suggest that combination therapy with a Rho-Kinase Inhibitor and prostacyclin exerts further beneficial effects on PH.
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transforming growth factor β2 and connective tissue growth factor in proliferative vitreoretinal diseases possible involvement of hyalocytes and therapeutic potential of Rho Kinase Inhibitor
Diabetes, 2007Co-Authors: Takeshi Kita, Hiroaki Shimokawa, Yasuaki Hata, Muneki Miura, Shintaro Nakao, Kumiko Kano, Yoshihiro Noda, Tatsuro IshibashiAbstract:The critical association of connective tissue growth factor (CTGF), which is thought to be one of the downstream mediators of transforming growth factor-β (TGF-β), with vitreoretinal diseases remains to be clarified. In the current study, we first demonstrated the correlation between the concentrations of TGF-β2 as well as CTGF in the vitreous and CTGF gene regulation in cultured hyalocytes. Concentrations of TGF-β2 and CTGF in the vitreous from patients with proliferative vitreoretinal diseases were significantly higher than in those with nonproliferative diseases, and there was a positive correlation between their concentrations ( r = 0.320, P < 0.01). Cultured hyalocytes expressed CTGF mRNA, which was enhanced in the presence of TGF-β2, associated with nuclear accumulation of Smad4. TGF-β2–dependent Smad4 translocation and CTGF gene expression were mediated through Rho Kinase and at least partially via p38 mitogen-activated protein Kinase. Finally, fasudil, a Rho Kinase Inhibitor already in clinical use, inhibited both Smad4 translocation and CTGF gene expression. In conclusion, combined effects of TGF-β2 and CTGF appear to be involved in the pathogenesis of proliferative vitreoretinal diseases. Hyalocytes may be a possible source of CTGF and thus might play a role in vitreoretinal interface diseases. Furthermore, Rho Kinase Inhibitors might have therapeutic potential to control fibrotic disorders in the eye.
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The selective Rho-Kinase Inhibitor Fasudil is protective and therapeutic in experimental autoimmune encephalomyelitis.
Journal of Neuroimmunology, 2006Co-Authors: Xiaojia Sun, Hiroaki Shimokawa, Motozumi Minohara, Hitoshi Kikuchi, Takaaki Ishizu, Masahito Tanaka, Hua Piao, Manabu Osoegawa, Yasumasa Ohyagi, Jun Ichi KiraAbstract:We studied the role of fasudil, a selective Rho-Kinase Inhibitor, in experimental autoimmune encephalomyelitis (EAE). Both parenteral and oral administration of fasudil prevented the development of EAE induced by proteolipid protein (PLP) p139-151 in SJL/J mice. Specific proliferation of lymphocytes to PLP was significantly reduced, together with a downregulation of interleukin (IL)-17 and a marked decrease of the IFN-gamma/IL-4 ratio. Immunohistochemical examination also disclosed a marked decrease of inflammatory cell infiltration, and attenuated demyelination and acute axonal transaction. These results may provide a rationale of selective blockade of Rho-Kinase by oral use of fasudil as a new therapy for multiple sclerosis.
Klaas Poelstra - One of the best experts on this subject based on the ideXlab platform.
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Increased liver uptake and reduced hepatic stellate cell activation with a cell-specific conjugate of the Rho-Kinase Inhibitor Y27632.
Pharmaceutical research, 2011Co-Authors: Marike Van Beuge, Jai Prakash, Marie Lacombe, Eduard Post, Catharina Reker-smit, Leonie Beljaars, Klaas PoelstraAbstract:Purpose Rho-Kinase regulates activation of hepatic stellate cells (HSC) during liver fibrosis, but the ubiquitous presence of this Kinase may hinder examination of its exact role and the therapeutic use of Inhibitors. We therefore coupled the Rho-Kinase Inhibitor Y27632 to a drug carrier that binds the mannose-6-phosphate insulin-like growth factor II (M6P/IGFII)-receptor which is upregulated on activated HSC.
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Reduction of fibrogenesis by selective delivery of a Rho-Kinase Inhibitor to hepatic stellate cells in mice.
The Journal of pharmacology and experimental therapeutics, 2011Co-Authors: M. M. Van Beuge, Jai Prakash, Marie Lacombe, Eduard Post, Catharina Reker-smit, Leonie Beljaars, Reinoud Gosens, Klaas PoelstraAbstract:One of the pathways activated during liver fibrosis is the Rho Kinase pathway, which regulates activation, migration, and contraction of hepatic stellate cells (HSC). Inhibition of this Kinase by the Rho Kinase Inhibitor Y27632 [(+)-(R)-trans- 4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride] has been shown to reduce fibrosis in animal models. However, Kinase expression is ubiquitous, so any Inhibitor may affect many cell types. We hypothesize that cell-specific delivery of a Kinase Inhibitor will be beneficial. Therefore, we conjugated Y27632 to the carrier mannose-6-phosphate (M6P) human serum albumin (HSA), which is taken up specifically in activated HSC through the M6P/insulin-like growth factor II receptor. This conjugate decreased protein expression of phosphorylated myosin light chain 2 (pMLC2) and vinculin, downstream of Rho Kinase, in activated primary HSC and decreased the migration and contraction of HSC. In an ex vivo model, free Y27632 decreased contractility of rat aortas, whereas the Y27-conjugate did not, showing that the Y27-conjugate does not affect nontarget tissue. In chronic CCl(4)-induced liver fibrosis, both free drug and conjugate reduced HSC activation; however, only the Y27-conjugate significantly reduced collagen deposition. Treatment with the Y27-conjugate, but not with free drug, reduced pMLC2 expression in livers 24 h after injection, demonstrating prolonged inhibition of the Rho Kinase pathway. The Rho Kinase Inhibitor Y27632 can be specifically targeted to HSC using M6PHSA, decreasing its effects in nontarget tissues. The targeted drug effectively reduced fibrotic parameters in vivo via the inhibition of the Rho Kinase pathway.
Akira Takeshita - One of the best experts on this subject based on the ideXlab platform.
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long term treatment with a specific Rho Kinase Inhibitor suppresses cardiac allograft vasculopathy in mice
Circulation Research, 2004Co-Authors: Tsuyoshi Hattori, Hiroaki Shimokawa, Midoriko Higashi, Junko Hiroki, Yasushi Mukai, Kozo Kaibuchi, Akira TakeshitaAbstract:Cardiac allograft vasculopathy (CAV) continues to be a major cause of late graft failure after cardiac transplantation. We have demonstrated that Rho-Kinase, an effector of the small GTPase Rho, plays an important role in the pathogenesis of arteriosclerosis. In this study, we examined whether the Rho-Kinase-mediated pathway is also involved in the pathogenesis of CAV using a specific Rho-Kinase Inhibitor and a dominant-negative Rho-Kinase. Hearts from AKR mice were heterotopically transplanted to C3H/He (allograft) or AKR mice (isograft), and the effects of long-term oral treatment with fasudil, which is metabolized to a specific Rho-Kinase Inhibitor hydroxyfasudil, on CAV were examined at 2 and 4 weeks after the transplantation. Coronary remodeling in the allografts characterized by intimal thickening and perivascular fibrosis was dose-dependently suppressed in the fasudil group compared with the control group (P<0.01, n=9 to 10). The Inhibitory effects of hydroxyfasudil were mimicked by in vivo gene transfer of dominant-negative Rho-Kinase (P<0.05, n=4). Among the proinflammatory cytokines examined, those of macrophage migration Inhibitory factor, interferon-gamma, and transforming growth factor-beta1 were upregulated in the control group and were dose-dependently inhibited in the fasudil group (P<0.01, n=5). Vascular inflammation in the allografts, as evidenced by accumulation of inflammatory cells (macrophages and T cells), was also significantly inhibited in the fasudil group (P<0.05, n=5 to 10). These results indicate that long-term treatment with fasudil suppresses CAV in mice, suggesting that Rho-Kinase is an important therapeutic target for the prevention of CAV.
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Long-Term Treatment With a Specific Rho-Kinase Inhibitor Suppresses Cardiac Allograft Vasculopathy in Mice
Circulation research, 2003Co-Authors: Tsuyoshi Hattori, Hiroaki Shimokawa, Midoriko Higashi, Junko Hiroki, Yasushi Mukai, Kozo Kaibuchi, Akira TakeshitaAbstract:Cardiac allograft vasculopathy (CAV) continues to be a major cause of late graft failure after cardiac transplantation. We have demonstrated that Rho-Kinase, an effector of the small GTPase Rho, plays an important role in the pathogenesis of arteriosclerosis. In this study, we examined whether the Rho-Kinase-mediated pathway is also involved in the pathogenesis of CAV using a specific Rho-Kinase Inhibitor and a dominant-negative Rho-Kinase. Hearts from AKR mice were heterotopically transplanted to C3H/He (allograft) or AKR mice (isograft), and the effects of long-term oral treatment with fasudil, which is metabolized to a specific Rho-Kinase Inhibitor hydroxyfasudil, on CAV were examined at 2 and 4 weeks after the transplantation. Coronary remodeling in the allografts characterized by intimal thickening and perivascular fibrosis was dose-dependently suppressed in the fasudil group compared with the control group (P
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suppression of coronary artery spasm by the Rho Kinase Inhibitor fasudil in patients with vasospastic angina
Circulation, 2002Co-Authors: Akihiro Masumoto, Hiroaki Shimokawa, Masahiro Mohri, Lemmy Urakami, Makoto Usui, Akira TakeshitaAbstract:Background— Increased activity of Rho-Kinase causes hypercontraction of vascular smooth muscle and has been implicated as playing a pathogenetic role in divergent cardiovascular diseases such as coronary artery spasm. We examined whether an intracoronary infusion of fasudil, a selective Rho-Kinase Inhibitor, would attenuate coronary vasoconstrictor responses to acetylcholine (ACh) in patients with vasospastic angina. Methods and Results— We studied 20 consecutive patients in whom coronary artery spasm was provoked by intracoronary ACh. The patients underwent a second ACh challenge after pretreatment with intracoronary saline (n=5) or fasudil (n=15; 300 μg/min for 15 minutes). Angina and coronary vasospasm were reproducibly induced by the second testing in patients who received saline. In contrast, fasudil markedly attenuated the coronary constriction induced by ACh (P<0.001) and prevented the occurrence of chest pain and ischemic ECG changes in all treated patients (both P<0.01 versus saline). Fasudil, at...
Hidenobu Tanihara - One of the best experts on this subject based on the ideXlab platform.
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the effects of ripasudil k 115 a Rho Kinase Inhibitor on activation of human conjunctival fibroblasts
Experimental Eye Research, 2016Co-Authors: Akiko Futakuchi, Toshihiro Inoue, Tomokazu Fujimoto, Miyuki Inouemochita, Motofumi Kawai, Hidenobu TaniharaAbstract:The most common cause of glaucoma surgery failure is scar formation induced by activation of wound-healing responses and resultant fibrosis at the surgical site. We investigated the effects of ripasudil, a Rho Kinase Inhibitor, on activation of human conjunctival fibroblasts (HConF). HConF were pretreated with different concentrations of ripasudil for 1 h before addition of transforming growth factor (TGF)-β2, followed by incubation for 48 h. TGF-β2-treated fibroblasts exhibited a significant increase in expression of α-smooth muscle actin (α-SMA), a marker of fibroblast-to-myofibroblast differentiation, and this increase was significantly suppressed, in a dose-dependent manner, by pretreatment with ripasudil. Ripasudil pretreatment also significantly attenuated TGF-β2-induced fibronectin production and collagen gel contraction. TGF-β2 increased both the number of viable cells and the number of cells in the G2/M phase of the cell cycle; these effects were attenuated by pretreatment with ripasudil. In addition, we explored the effects of ripasudil on stimulation of HConF by activated macrophages. Human monocytic cell line THP-1 cells were differentiated into M1 or M2 macrophage-like cells, and HConF were treated with conditioned media derived from these macrophages in the presence or absence of ripasudil. Conditioned medium from M2 macrophage-like cells induced a significant increase in α-SMA expression, viable cell numbers, and gel contraction, all of which were significantly suppressed by ripasudil. Thus, overall, ripasudil attenuated activation of human conjunctival fibroblasts. Ripasudil may be of therapeutic utility, preventing excessive scarring after glaucoma filtration surgery.
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Phase 1 clinical trials of a selective Rho Kinase Inhibitor, K-115.
JAMA ophthalmology, 2013Co-Authors: Hidenobu Tanihara, Toshihiro Inoue, Tetsuya Yamamoto, Yasuaki Kuwayama, Haruki Abe, Makoto AraieAbstract:We conducted a series of phase 1 clinical trials to elucidate the efficacy and safety of the selective Rho Kinase Inhibitor K-115 as a candidate drug for the treatment of glaucoma. We report the intraocular pressure (IOP)-lowering effects and safety of K-115 based on our results. To study the IOP-lowering effects and safety of topical administration of a selective Rho Kinase Inhibitor, K-115, in healthy male adult volunteers. Randomized, placebo-controlled, double-masked, group comparison phase 1 clinical trial. In the initial single-instillation trial, 50 healthy volunteers were subdivided into groups and treated with placebo or K-115 in concentrations of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8% in a stepwise manner. In the repeated-instillation trial, another 50 healthy volunteers were subdivided into groups and treated with placebo or K-115 in concentrations of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8% twice daily for 7 days in a stepwise manner. In these clinical trials, the administration of eyedrops and associated examinations (including IOP measurements) were performed in a double-masked manner. After single instillation of placebo or K-115 in concentrations of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8%, the changes in IOP from baseline were -1.6 mm Hg for placebo and -3.4, -2.2, -2.6, -4.0, and -4.3 mm Hg, respectively, for the different concentrations 2 hours after instillation. Similar to the single-instillation trial, IOP reductions in the repeated-instillation trial were found after each instillation, with maximal reduction 1 to 2 hours after instillation. In the safety trial, slight to mild conjunctival hyperemia was found in more than half of the participants treated with K-115; it was found after each instillation and spontaneously resolved within 1½ hours. K-115 is a promising drug for lowering IOP in healthy adult eyes, with tolerable adverse events during at least short-term administration.
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phase 1 clinical trials of a selective Rho Kinase Inhibitor k 115
JAMA Ophthalmology, 2013Co-Authors: Hidenobu Tanihara, Toshihiro Inoue, Tetsuya Yamamoto, Yasuaki Kuwayama, Haruki Abe, Makoto AraieAbstract:Importance We conducted a series of phase 1 clinical trials to elucidate the efficacy and safety of the selective Rho Kinase Inhibitor K-115 as a candidate drug for the treatment of glaucoma. We report the intraocular pressure (IOP)–lowering effects and safety of K-115 based on our results. Objective To study the IOP-lowering effects and safety of topical administration of a selective Rho Kinase Inhibitor, K-115, in healthy male adult volunteers. Design and Setting Randomized, placebo-controlled, double-masked, group comparison phase 1 clinical trial. Participants In the initial single-instillation trial, 50 healthy volunteers were subdivided into groups and treated with placebo or K-115 in concentrations of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8% in a stepwise manner. In the repeated-instillation trial, another 50 healthy volunteers were subdivided into groups and treated with placebo or K-115 in concentrations of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8% twice daily for 7 days in a stepwise manner. Main Outcomes and Measures In these clinical trials, the administration of eyedrops and associated examinations (including IOP measurements) were performed in a double-masked manner. Results After single instillation of placebo or K-115 in concentrations of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8%, the changes in IOP from baseline were −1.6 mm Hg for placebo and −3.4, −2.2, −2.6, −4.0, and −4.3 mm Hg, respectively, for the different concentrations 2 hours after instillation. Similar to the single-instillation trial, IOP reductions in the repeated-instillation trial were found after each instillation, with maximal reduction 1 to 2 hours after instillation. In the safety trial, slight to mild conjunctival hyperemia was found in more than half of the participants treated with K-115; it was found after each instillation and spontaneously resolved within 1½ hours. Conclusions and Relevance K-115 is a promising drug for lowering IOP in healthy adult eyes, with tolerable adverse events during at least short-term administration.
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phase 2 randomized clinical study of a Rho Kinase Inhibitor k 115 in primary open angle glaucoma and ocular hypertension
American Journal of Ophthalmology, 2013Co-Authors: Hidenobu Tanihara, Toshihiro Inoue, Tetsuya Yamamoto, Yasuaki Kuwayama, Haruki Abe, Makoto AraieAbstract:Purpose To identify the optimal dose of a novel Rho Kinase Inhibitor, K-115, by assessing dose dependency of the intraocular pressure (IOP)-lowering effects and the safety in patients with primary open-angle glaucoma or ocular hypertension. Designs Multicenter, prospective, randomized, placebo-controlled, double-masked, parallel group comparison clinical study. Methods After appropriate washout periods, 210 patients with primary open-angle glaucoma or ocular hypertension were subdivided into 4 groups and were treated with K-115 in concentrations of 0.1%, 0.2%, and 0.4% or placebo twice daily for 8 weeks. The dose response of IOP reduction and the incidence of adverse events by K-115 or placebo were investigated. Results The mean baseline IOP was between 23.0 and 23.4 mm Hg. The mean IOP reductions of the last visit from baseline were −2.2 mm Hg, −3.4 mm Hg, −3.2 mm Hg, and −3.5 mm Hg, respectively, in the placebo, 0.1%, 0.2%, and 0.4% groups at before instillation (9:00); −2.5 mm Hg, −3.7 mm Hg, −4.2 mm Hg, and −4.5 mm Hg at 2 hours after instillation (11:00); and −1.9 mm Hg, −3.2 mm Hg, −2.7 mm Hg, and −3.1 mm Hg at 8 hours after instillation (17:00). The dose-dependent IOP-lowering effect of K-115 was statistically significant at all time points. Also, conjunctival hyperemia was found in 7 (13.0%) of 54 patients for placebo, 23 (43.4%) of 53 patients for the 0.1% group, 31 (57.4%) of 54 patients for the 0.2% group, and 32 (65.3%) of 49 patients for the 0.4% group. Conclusions On the basis of this dose-response study, K-115 0.4% has been selected to be the optimal dose and has the potential to be a promising new agent for glaucoma to control 24-hour IOP by twice-daily dosing.
Yoshihiro Fukumoto - One of the best experts on this subject based on the ideXlab platform.
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double blind placebo controlled clinical trial with a Rho Kinase Inhibitor in pulmonary arterial hypertension
Circulation, 2013Co-Authors: Yoshihiro Fukumoto, Norikazu Yamada, Hiromi Matsubara, Minori Mizoguchi, Kazuaki Uchino, Atsushi Yao, Yasuki Kihara, Mitsuhiro Kawano, Hiroshi Watanabe, Yutaka TakedaAbstract:Background: We have previously demonstrated that long-term inhibition of Rho-Kinase ameliorates pulmonary arterial hypertension (PAH) in animal models. In the present study, we examined the clinical effects of mid-term oral treatment with an extended release formulation of AT-877 (fasudil hydrochloride), a specific Rho-Kinase Inhibitor (AT-877ER) on PAH. Methods and Results: 23 PAH patients were treated with either placebo (10/2 females/males, 51±16 years, idiopathic PAH (IPAH) in 6, PAH associated with connective tissue disease (CTD-PAH) in 3, PAH with congenital heart disease (CHD-PAH) in 2, and portal PAH in 1) or AT-877ER (6/5 females/males, 47±14 years, IPAH in 2, CTD-PAH in 5, and CHD-PAH in 4); 3 patients were excluded. We performed a 6-min walk test and right heart catheterization in the remaining 20 patients, before and 3 months after the treatment (placebo n=11, AT-877ER n=9). Although there were no significant differences between the 2 groups for the 6-min walk distance, pulmonary hemodynamics tended to be improved in the AT-877ER group, especially the prevalence of improved cardiac index from baseline, which was significantly higher in the AT-877ER than in the placebo group. In the AT-877ER group, serum levels of hydroxyfasudil, an active metabolite of AT-877ER tended to correlate with improvements in the cardiac index and mean pulmonary artery pressure. Conclusions: Mid-term treatment with oral AT-877ER showed additional improvement in pulmonary hemodynamics in patients with PAH. (Circ J 2013; 77: 2619–2625)
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acute vasodilator effects of inhaled fasudil a specific Rho Kinase Inhibitor in patients with pulmonary arterial hypertension
Heart and Vessels, 2010Co-Authors: Hiroshi Fujita, Yoshihiro Fukumoto, Kenya Saji, Koichiro Sugimura, Jun Demachi, Jun Nawata, Hiroaki ShimokawaAbstract:We have previously demonstrated that long-term inhibition of Rho-Kinase ameliorates pulmonary arterial hypertension (PAH) in animal models. In the present study, we examined acute vasodilator effects of inhaled fasudil, a specific Rho-Kinase Inhibitor, as a more feasible option to locally deliver the drug for PAH. We examined 15 patients with PAH (13 women and 2 men, 45 ± 4 years old), including idiopathic PAH (n = 5), PAH associated with connective tissue disease (n = 6), PAH with congenital heart disease (n = 3), and portal PAH (n = 1). In those patients, we performed right heart catheterization with a Swan-Ganz catheter in the two protocols with inhalation of nitric oxide (NO) (40 ppm, 10 min) and fasudil (30 mg, 10 min) with a sufficient interval (>30 min). Both NO and fasudil inhalation significantly reduced mean pulmonary arterial pressure (PAP) (NO: P < 0.01, fasudil: P < 0.05) and tended to decrease pulmonary vascular resistance (NO: P = 0.07, fasudil: P = 0.1), but did not affect cardiac index. The ratio of pulmonary to systemic vascular resistance was significantly reduced both in NO and fasudil inhalation (NO: P < 0.01, fasudil: P < 0.05), indicating that both NO and fasudil inhalation selectively affect lung tissues. Interestingly, there was no correlation in the vasodilator effects between NO and fasudil, and a positive correlation with serum levels of high-sensitivity C-reactive protein was noted for fasudil but not for NO. These results suggest that inhalation of fasudil is as effective as NO in patients with PAH, possibly through different mechanisms.
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acute vasodilator effect of fasudil a Rho Kinase Inhibitor in monocrotaline induced pulmonary hypertension in rats
Journal of Cardiovascular Pharmacology, 2007Co-Authors: Bao Hua Jiang, Hiroaki Shimokawa, Shunsuke Tawara, Yoshihiro Fukumoto, Kohtaro Abe, Aya TakakiAbstract:Pulmonary arterial hypertension is a progressive and fatal disease for which Rho-Kinase may be substantially involved. In this study, we examined the acute vasodilator effects of fasudil, a Rho-Kinase Inhibitor, in monocrotaline (MCT)-induced pulmonary hypertension (PH) in rats. Three weeks after a single subcutaneous injection of MCT (60 mg/kg), hemodynamic variables were measured under conscious and free-moving conditions before and after oral administration of fasudil. MCT caused a significant elevation of mean pulmonary arterial pressure (mPAP). Although a low dose of fasudil (3 mg/kg) had no effect on mPAP, a middle dose (10 mg/kg) caused a significant reduction in mPAP without change in mean systemic arterial pressure (mSAP), and a high dose (30 mg/kg) significantly reduced both mPAP and mSAP. Rho-Kinase activity was significantly increased by MCT injection in pulmonary arteries but not in the aorta. Fasudil (10 mg/kg) inhibited only the Rho-Kinase activity in pulmonary arteries without any effect in the aorta. Plasma concentration of hydroxyfasudil, a metabolite of fasudil, was within its clinical range in humans. These results demonstrate that fasudil exerts effective and selective vasodilatation of pulmonary arteries in rats with MCT-induced PH at a given dose, suggesting its usefulness for the treatment of the fatal disorder.
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Effects of combined therapy with a Rho-Kinase Inhibitor and prostacyclin on monocrotaline-induced pulmonary hypertension in rats.
Journal of cardiovascular pharmacology, 2007Co-Authors: Shunsuke Tawara, Yoshihiro Fukumoto, Hiroaki ShimokawaAbstract:Pulmonary hypertension (PH) is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells, and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have previously demonstrated that long-term inhibition of Rho-Kinase, an effector of the small GTPase Rho, ameliorates monocrotaline-induced PH in rats and hypoxia-induced PH in mice. We also have reported that prostacyclin and its oral analogue, beraprost sodium (BPS), may lack direct Inhibitory effect on Rho-Kinase in vitro, suggesting that combination therapy with a Rho-Kinase Inhibitor and BPS is effective for the treatment of PH. In this study, we addressed this point in monocrotaline-induced PH model in rats. Male Sprague-Dawley rats were given a subcutaneous injection of monocrotaline (60 mg/kg). They were maintained with or without the treatment with a Rho-Kinase Inhibitor, fasudil (30 mg/kg/day), BPS (200 microg/kg/day), or a combination of both drugs for 3 weeks. The combination therapy, when compared with each monotherapy, showed significantly more improvement in PH, right ventricular hypertrophy, and pulmonary medial thickness without any adverse effects. Plasma concentrations of fasudil were not affected by BPS. These results suggest that combination therapy with a Rho-Kinase Inhibitor and prostacyclin exerts further beneficial effects on PH.
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usefulness of fasudil a Rho Kinase Inhibitor to treat intractable severe coronary spasm after coronary artery bypass surgery
Journal of Cardiovascular Pharmacology, 2004Co-Authors: Kousuke Inokuchi, Yoshihiro Fukumoto, Akira Ito, Tetsuya Matoba, Akira Shiose, Takahiro Nishida, Munetaka Masuda, Shigeki Morita, Hiroaki ShimokawaAbstract:We have recently demonstrated that fasudil, a Rho-Kinase Inhibitor, is effective in suppressing coronary artery spasm in patients with vasospastic angina. Thus, blockade of Rho-Kinase may provide a novel therapeutic strategy to treat ischemic coronary syndrome caused by the spasm. Severe coronary artery spasm still remains a life-threatening serious complication of coronary artery bypass grafting (CABG). In this study, we examined the Inhibitory effect of fasudil in patients with intractable severe coronary spasm after CABG. Three patients who underwent CABG showed severe myocardial ischemia resistant to intensive therapy with intravenous conventional vasodilators, including isosorbide dinitrate (ISDN), diltiazem, and nicorandil. Coronary angiography revealed severe coronary spasm in native coronary arteries and/or bypass arterial grafts in all patients. Since intracoronary and/or intragraft administration of ISDN was ineffective to resolve the spasm, we then administered fasudil (1.5 mg/min for 15 minutes) into the spastic arteries. Fasudil successfully resolved the spasm and improved myocardial ischemia in all patients without any systemic adverse effects. In conclusion, the treatment with fasudil may be useful to treat intractable and otherwise fatal coronary spasm resistant to intensive conventional vasodilator therapy after CABG.