Fasudil Group Research Articles

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

Sub-analysis of the fasudil post-marketing surveillance study compared the safety and efficacy of fasudil plus ozagrel to fasudil only. A total of 3690 patients received fasudil and 1138 received fasudil plus ozagrel between 1995 and 2000. The occurrence of adverse events, occurrence of low density areas associated with vasospasm on computed tomography, absence of symptomatic vasospasm, and poor clinical outcomes associated with vasospasm were compared between the fasudil and fasudil plus ozagrel groups. The pharmacokinetics of fasudil were assessed in 5 patients with subarachnoid hemorrhage. The drug interaction between fasudil and ozagrel was pharmacologically investigated in vitro and in vivo. The occurrence of adverse events and clinical outcomes were similar between the two groups. The occurrences of symptomatic vasospasm and low density areas were lower in the fasudil group than in the fasudil plus ozagrel group. The average trough value (8-hour value) of the fasudil active metabolite, hydroxyfasudil, was 50 nM. Fasudil showed no pharmacological interaction with ozagrel. The combination of fasudil plus ozagrel was well tolerated, but did not result in better efficacy than fasudil only.

Fasudil Attenuates Myocardial Fibrosis in Association With Inhibition of Monocyte/Macrophage Infiltration in the Heart of DOCA/Salt Hypertensive Rats

To determine the effects of fasudil, a Rho-kinase inhibitor, on mineralocorticoid-induced myocardial remodeling, we investigated whether fasudil would suppress myocardial fibrosis and inflammation in deoxycorticosterone-acetate (DOCA)/salt hypertensive rats. Sprague-Dawley rats treated with DOCA combined with 1% NaCl and 0.2% KCl in the drinking water after receiving left nephrectomy were given fasudil (10 mg/kg/day; n = 20) or vehicle (n = 20). Systolic blood pressure (SBP) was measured biweekly. Myocardial monocyte/macrophage infiltration and myocardial fibrosis were determined histologically. Expressions of mRNA of procollagen I (PI), procollagen III (PIII), monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6, type-1 plasminogen activator inhibitor (PAI-1), transforming growth factor (TGF)-beta1, and c-fos were determined. SBP was significantly increased on day 14 after treatment with DOCA/salt. Extent of interstitial and perivascular fibrosis was significantly increased on day 28. Expressions of mRNA of PI, PIII, MCP-1, IL-6, PAI-1, TGF-beta1, and c-fos were significantly increased on day 14. Although SBP did not differ between the fasudil and vehicle groups, extent of monocyte/macrophage infiltration and fibrosis was attenuated in the fasudil group. Expressions of mRNA of these factors except TGF-beta1 were also attenuated. Fasudil attenuates myocardial fibrosis possibly via suppression of monocyte/macrophage infiltration of the heart in DOCA/salt hypertensive rats.

Long-term inhibition of Rho kinase suppresses intimal thickening in autologous vein grafts in rabbits

Rho kinase plays an important role in vascular smooth muscle cell (VSMC) contraction and other cellular functions, such as proliferation, migration, and apoptosis. Recent studies have demonstrated that long-term inhibition of Rho kinase suppresses coronary artery spasm and vascular lesion formation after arterial injury. In the cardiovascular surgery field, intimal thickening in vein grafts is the major cause of late graft failure, for which no effective treatment has yet been developed. In this study, we examined whether long-term inhibition of Rho kinase suppresses intimal thickening in autologous vein grafts in rabbits. Male rabbits were randomly divided into two groups and received normal chow (control group) or a special chow containing 0.09% fasudil (fasudil group). After oral administration, fasudil is metabolized to a specific Rho kinase inhibitor, hydroxyfasudil. Each group underwent reversed autologous vein graft surgery with the internal jugular vein into the left common carotid artery. At 1, 2, and 4 weeks after the operation, we examined the extent of intimal thickening of the graft and VSMC proliferation and apoptosis. The intimal thickening was significantly suppressed in the fasudil group compared with the control group at 2 and 4 weeks after the operation. In the fasudil group, VSMC proliferation was suppressed at 1 and 2 weeks after the operation, whereas VSMC apoptosis was enhanced at 2 weeks after the procedure. These results indicate that Rho kinase is substantially involved in the pathogenesis of intimal thickening of vein grafts and that it is an important therapeutic target for the prevention of graft failure.

Effect of Fasudil Hydrochloride, a Protein Kinase Inhibitor, on Cerebral Vasospasm and Delayed Cerebral Ischemic Symptoms After Aneurysmal Subarachnoid Hemorrhage-Results of a Randomized Trial of Fasudil Hydrochloride Versus Nimodipine-

The efficacy and safety of fasudil hydrochloride, a novel protein kinase inhibitor, were evaluated for the treatment of cerebral vasospasm and associated cerebral ischemic symptoms in patients with ruptured cerebral aneurysm. This randomized open trial with nimodipine as the control included 72 patients who underwent subarachnoid hemorrhage surgery for ruptured cerebral aneurysm of Hunt and Hess grades I to IV. For 14 days following surgery, patients were administered either 30 mg of fasudil hydrochloride by intravenous injection over a period of 30 minutes three times a day or 1 mg/hr of nimodipine by continuous intravenous infusion. Fasudil hydrochloride and nimodipine both showed inhibitory effects on cerebral vasospasm. The incidence of symptomatic vasospasm was five of 33 patients in the fasudil group and nine of 32 patients in the nimodipine group. Good recovery evaluated by the Glasgow Outcome Scale was achieved by 23 of 33 patients in the fasudil group and 19 of 34 patients in the nimodipine group. Both drugs significantly improved consciousness levels and neurological deficits such as aphasia. However, fasudil hydrochloride improved motor disturbance more than nimodipine. Adverse reactions occurred in 13 of 37 patients receiving fasudil hydrochloride and 15 of 35 patients receiving nimodipine. There were no serious adverse events in the fasudil group. The results of this clinical trial indicate that fasudil hydrochloride is a safe and efficient agent for suppressing cerebral vasospasm after subarachnoid hemorrhage surgery for ruptured cerebral aneurysm.

Effects of fasudil in acute ischemic stroke: Results of a prospective placebo-controlled double-blind trial

Background A multicenter, double-blind, placebo-controlled study was conducted to assess the efficacy and safety of fasudil, a Rho-kinase inhibitor (RKI), in the treatment of acute ischemic stroke. Methods A total of 160 patients, who were able to receive drug treatment within 48 h of acute ischemic stroke onset were enrolled. Patients received either 60 mg fasudil or a placebo (saline) by intravenous injection over 60 min, twice daily for 14 days. The primary end points were neurological status at 2 weeks after the start of treatment, and clinical outcome at 1 month after the onset of symptoms. Results Fasudil treatment resulted in significantly greater improvements in both neurological functions ( p = 0.0013), and clinical outcome ( p = 0.0015). There were no serious adverse events reported in the fasudil group. The average trough value (12 h values) of active metabolite hydroxyfasudil, another RKI, in healthy elderly volunteers receiving 60 mg of fasudil was 0.077 μM—a concentration well above that needed to inhibit Rho-kinase (0.025–0.05 μM). Conclusion Treatment with fasudil within 48 h of acute ischemic stroke onset significantly improved the patient's clinical outcome. This study found fasudil to be a useful and safe drug for patients with acute ischemic stroke. Further evaluations, for example, 3-month functional outcomes in a larger clinical trial, may help to define the efficacy of fasudil in acute ischemic stroke.

Inhibition of Rho-kinase by fasudil attenuated angiotensin II-induced cardiac hypertrophy in apolipoprotein E deficient mice

Recent evidence indicates that the GTPase activated Rho/Rho-kinase pathway contributes angiotensin II-induced cardiac hypertrophy and vascular remodeling. We tested this hypothesis in vivo by determining the effects of fasudil, a Rho-kinase inhibitor, on angiotensin II-induced cardiac hypertrophy, coronary vascular remodeling, and ventricular dysfunction. Six-month-old apolipoprotein E deficient (apoE-KO) mice were subcutaneously infused with angiotensin II (1.44 mg/kg/day) using an osmotic mini-pump. Mice were randomly assigned to either vehicle or fasudil (136 or 213 mg/kg/day in drinking water) group. Infusion of angiotensin II for 4 weeks resulted in cardiac enlargement, myocyte hypertrophy, and myocardial interstitial and coronary artery perivascular fibrosis. These changes were accompanied by reduced aortic flow velocity and acceleration rate. Cardiac gene expression levels of atrial natriuretic peptide (ANP) and collagen type III detected by real-time reverse transcriptase polymerase chain reaction were significantly increased in angiotensin II-infused mice. Treatment with fasudil dose-dependently attenuated angiotensin II-induced cardiac hypertrophy, prevented perivascular fibrosis, blunted the increase in ANP and collagen type III expression, and improved cardiac function, without changing blood pressure. These data are consistent with a role for Rho-kinase activation in angiotensin II-induced cardiac remodeling and vascular wall fibrosis.

Long-term inhibition of Rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice.

Rho-kinase has been implicated as an important regulator of inflammatory responses mediated by cytokines and chemokines. Because proinflammatory cytokines play a critical role in left ventricular (LV) remodeling after myocardial infarction (MI), we examined whether long-term blockade of Rho-kinase suppresses LV remodeling in a mouse model of MI in vivo. Mice underwent ligation of the left coronary artery and were treated with a Rho-kinase inhibitor, fasudil (100 mg x kg(-1) x d(-1) in tap water), for 4 weeks, starting 1 day after the surgery. At 4 weeks, LV infarct size was histologically comparable between the 2 groups. LV cavity dilatation and dysfunction evaluated by echocardiography were significantly suppressed in the fasudil group (P<0.05, n=15 to 28). The beneficial effects of fasudil were accompanied by suppression of cardiomyocyte hypertrophy and interstitial fibrosis (both P<0.01, n=6). The expression of inflammatory cytokines, including transforming growth factor (TGF)-beta2, TGF-beta3, and macrophage migration inhibitory factor, was upregulated in the noninfarcted LV in the control group and was significantly suppressed in the fasudil group (both P<0.05, n=10 to 11). Rho-kinase activity as evaluated by the extent of phosphorylation of the ERM family, a substrate of Rho-kinase, was significantly increased in the noninfarcted LV in the control group and was significantly suppressed in the fasudil group (P<0.05, n=5). These results indicate that Rho-kinase is substantially involved in the pathogenesis of LV remodeling after MI associated with upregulation of proinflammatory cytokines, suggesting a therapeutic importance of the molecule for the prevention of post-MI heart failure.

Long-term treatment with a specific Rho-kinase inhibitor suppresses cardiac allograft vasculopathy in mice.

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.

Long-term inhibition of Rho-kinase induces a regression of arteriosclerotic coronary lesions in a porcine model in vivo.

We recently demonstrated that Rho-kinase/ROK/ROCK is functionally upregulated at the arteriosclerotic coronary lesions and plays a key role for coronary vasospastic responses in our porcine model with interleukin (IL)-1beta. In the present study, we tested our hypothesis that Rho-kinase is involved in the pathogenesis of coronary arteriosclerosis per se in our porcine model. Segments of the left porcine coronary artery were chronically treated from the adventitia with IL-1beta. Two weeks after the procedure, coronary stenotic lesions with constrictive remodeling and vasospastic response to serotonin were noted at the IL-1beta-treated site, as previously reported. Then, animals were randomly divided into two groups; one group was treated with fasudil for 8 weeks followed by 1 or 4 weeks of washout period and another group served as a control. After oral absorption, fasudil is metabolized to hydroxyfasudil that is a specific inhibitor of Rho-kinase. In the fasudil group, coronary stenosis and vasospastic response were progressively reduced in vivo, while the coronary hyperreactivity was abolished both in vivo and in vitro. Furthermore, Western blot analysis showed that in the fasudil group, the Rho-kinase activity (as evaluated by the extent of phosphorylation of myosin binding subunit of myosin phosphatase, one of the major substrates of Rho-kinase) was significantly reduced, while histological examination demonstrated a marked regression of the coronary constrictive remodeling. These results indicate that Rho-kinase is substantially involved in constrictive remodeling and vasospastic activity of the arteriosclerotic coronary artery, both of which could be reversed by long-term inhibition of the molecule in vivo. Thus, Rho-kinase may be regarded as a novel therapeutic target for arteriosclerotic vascular disease.