Fasudil hydrochloride (FH) has been developed as an antivasospasm agent. Its dynamics in cerebrospinal fluid (CSF) and the vasodilating action of hydroxyfasudil (M3) have been obscure, although FH dilates spastic ateries from the inside of the vessel wall. The present study investigated concentrations of FH and M3 in serum and CSF. Dynamic studies of FH and M3 in the CSF of 10 patients with subarachnoid hemorrhage were conducted. FH (30 mg) was injected intravenously for 30 minutes, 3 times a day. Intra-arterial injection using a microcatheter from intracranial portions of the internal carotid artery was added to 3 patients with severe vasospasm. M3 remained in the serum longer than FH. Approximately 20% of the FH and M3 was transferred to CSF and remained there for a long time. The intra-arterial injections significantly increased M3 levels in CSF. These basic data may be helpful in developing future treatments.
"HA-1077 (Fasudil) is a ROCK inhibitor approved for clinical use in Japan. It is employed to suppress vasospasm in subarachnoid hemorrhage , , . We have previously observed that HA-1077 is more effective than Y-27632 in suppressing phosphorylation of profilin at Ser-137. "
[Show abstract][Hide abstract] ABSTRACT: Huntington disease (HD) is an inherited neurodegenerative disease that affects multiple brain regions. It is caused by an expanded polyglutamine tract in huntingtin (Htt). The development of therapies for HD and other neurodegenerative diseases has been hampered by multiple factors, including the lack of clear therapeutic targets, and the cost and complexity of testing lead compounds in vivo. The R6/2 HD mouse model is widely used for pre-clinical trials because of its progressive and robust neural dysfunction, which includes retinal degeneration. Profilin-1 is a Htt binding protein that inhibits Htt aggregation. Its binding to Htt is regulated by the rho-associated kinase (ROCK), which phosphorylates profilin at Ser-137. ROCK is thus a therapeutic target in HD. The ROCK inhibitor Y-27632 reduces Htt toxicity in fly and mouse models. Here we characterized the progressive retinopathy of R6/2 mice between 6-19 weeks of age to determine an optimal treatment window. We then tested a clinically approved ROCK inhibitor, HA-1077, administered intravitreally via liposome-mediated drug delivery. HA-1077 increased photopic and flicker ERG response amplitudes in R6/2 mice, but not in wild-type littermate controls. By targeting ROCK with a new inhibitor, and testing its effects in a novel in vivo model, these results validate the in vivo efficacy of a therapeutic candidate, and establish the feasibility of using the retina as a readout for CNS function in models of neurodegenerative disease.
PLoS ONE 02/2013; 8(2):e56026. DOI:10.1371/journal.pone.0056026 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Neuroimmunology 12/2006; 180(1-2):126-34. DOI:10.1016/j.jneuroim.2006.06.027 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A fast and sensitive method to quantify fasudil hydrochloride (FH) and its active metabolite hydroxyfasudil (M3) in human plasma using HPLC-MS/MS has been developed and validated in present study. The method involved simple sample preparation with methanol as protein precipitation (3:1, v/v) and ranitidine as an internal standard (IS). The analytes and IS were separated using a gradient elution procedure on the analytical column ZORBAX StableBond-C18 (5 microm, 150 mm x 4.6mm). Detection was performed by an AB 3200 QTRAP tandem mass spectrometer equipped with a Turbo IonSpray ionization source set in positive ion mode. Multiple reaction monitoring (MRM) using the precursor to product ion was m/z 292.2/99.2 for fasudil, m/z 308.2/99.2 for M3 and m/z for 315.3/176.2 for IS. The linear range of the method was from 0.4 to 250 ng/mL for both fasudil and M3. The lower limit of quantification was 0.4 ng/mL for both fasudil and M3. The intra- and inter-day relative standard deviation over the entire concentration range was less than 7.11% for fasudil and 10.6% for M3, respectively. The validated method was successfully applied for the evaluation of pharmacokinetic of fasudil hydrochloride after administration of 30 mg fasudil hydrochloride by continuous intravenous infusion over 30 min in 12 healthy Chinese volunteers.
Journal of pharmaceutical and biomedical analysis 06/2010; 52(2):242-8. DOI:10.1016/j.jpba.2009.12.028 · 2.98 Impact Factor
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