Combination Therapy of Fasudil Hydrochloride and Ozagrel Sodium for Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage

Nakashima, Satoru; Tabuchi, Kazuo; Shimokawa, S; Fukuyama, Kouzou; Mineta, Toshihiro; Abe, Masamitsu

doi:10.2176/nmc.38.805

Cited by 27 publications

(19 citation statements)

References 23 publications

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“…8) These results suggest that a combination therapy consisting of fasudil and ozagrel has superior efficacy for treating SAH patients. However, the present results indicated that the combination of fasudil plus ozagrel did not result in better efficacy than fasudil only.…”

Section: Efficacymentioning

confidence: 84%

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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

Suzuki

Shibuya

Satoh

et al. 2008

Neurol. Med. Chir.(Tokyo)

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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.

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Section: Efficacymentioning

confidence: 84%

“…2) Combination therapy using fasudil and ozagrel is reported to be effective. 8) The present sub-analysis of the fasudil PMS study compared the safety and efficacy of the combination of fasudil plus ozagrel with fasudil only to assess the interactions between fasudil and ozagrel in a large number of patients.…”

Section: Introductionmentioning

confidence: 99%

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

Shibuya

Satoh

et al. 2008

Neurol. Med. Chir.(Tokyo)

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“…Therefore, fasudil probably can move through the retina to inhibit rod axon terminals. Although fasudil originally was used for cerebral vasospasm, 33 intravitreal fasudil already has been applied to patients with diabetic macular edema and optic nerve damage to successfully interrupt vascular pathology. 34,35 Intravitreal injections of fasudil (10 μM) in patients showed no evidence of intraocular toxicity.…”

Section: Discussionmentioning

confidence: 99%

Fasudil, a Clinically Used ROCK Inhibitor, Stabilizes Rod Photoreceptor Synapses after Retinal Detachment

Townes‐Anderson

Wang

Halasz

et al. 2017

Trans. Vis. Sci. Tech.

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PurposeRetinal detachment disrupts the rod-bipolar synapse in the outer plexiform layer by retraction of rod axons. We showed that breakage is due to RhoA activation whereas inhibition of Rho kinase (ROCK), using Y27632, reduces synaptic damage. We test whether the ROCK inhibitor fasudil, used for other clinical applications, can prevent synaptic injury after detachment.MethodsDetachments were made in pigs by subretinal injection of balanced salt solution (BSS) or fasudil (1, 10 mM). In some animals, fasudil was injected intravitreally after BSS-induced detachment. After 2 to 4 hours, retinae were fixed for immunocytochemistry and confocal microscopy. Axon retraction was quantified by imaging synaptic vesicle label in the outer nuclear layer. Apoptosis was analyzed using propidium iodide staining. For biochemical analysis by Western blotting, retinal explants, detached from retinal pigmented epithelium, were cultured for 2 hours.ResultsSubretinal injection of fasudil (10 mM) reduced retraction of rod spherules by 51.3% compared to control detachments (n = 3 pigs, P = 0.002). Intravitreal injection of 10 mM fasudil, a more clinically feasible route of administration, also reduced retraction (28.7%, n = 5, P < 0.05). Controls had no photoreceptor degeneration at 2 hours, but by 4 hours apoptosis was evident. Fasudil 10 mM reduced pyknotic nuclei by 55.7% (n = 4, P < 0.001). Phosphorylation of cofilin and myosin light chain, downstream effectors of ROCK, was decreased with 30 μM fasudil (n = 8–10 explants, P < 0.05).ConclusionsInhibition of ROCK signaling with fasudil reduced photoreceptor degeneration and preserved the rod-bipolar synapse after retinal detachment.Translational RelevanceThese results support the possibility, previously tested with Y27632, that ROCK inhibition may attenuate synaptic damage in iatrogenic detachments.

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“…Although the clinical use of ROCK inhibitors is currently limited to the suppression of vascular constriction (Fujita et al, 2010), our recent data suggest that ILC with mutant E-cadherin (in contrast to E-cadherin-negative IDC) depend on ROCK signaling for the formation and dissemination of tumors (Schackmann et al, 2011). These findings might pave the way for clinical inhibition of ROCK signaling in specific tumor subtypes such as ILC using already clinically approved inhibitors, for instance fasudil (Nakashima et al, 1998). In such a setting, breast cancer patients with mutant E-cadherin and cytosolic p120 could be treated with ROCK inhibitors.…”

Section: Future Directions and Clinical Implicationsmentioning

confidence: 96%

p120-catenin in cancer – mechanisms, models and opportunities for intervention

Schackmann

Tenhagen

Ven

et al. 2013

Journal of Cell Science

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The epithelial adherens junction is an E-cadherin-based complex that controls tissue integrity and is stabilized at the plasma membrane by p120-catenin (p120, also known as CTNND1). Mutational and epigenetic inactivation of E-cadherin has been strongly implicated in the development and progression of cancer. In this setting, p120 translocates to the cytosol where it exerts oncogenic properties through aberrant regulation of Rho GTPases, growth factor receptor signaling and derepression of Kaiso (also known as ZBTB33) target genes. In contrast, indirect inactivation of the adherens junction through conditional knockout of p120 in mice was recently linked to tumor formation, indicating that p120 can also function as a tumor suppressor. Supporting these opposing functions are findings in human cancer, which show that either loss or cytoplasmic localization of p120 is a common feature in the progression of several types of carcinoma. Underlying this dual biological phenomenon might be the context-dependent regulation of Rho GTPases in the cytosol and the derepression of Kaiso target genes. Here, we discuss past and present findings that implicate p120 in the regulation of cancer progression and highlight opportunities for clinical intervention.

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Combination Therapy of Fasudil Hydrochloride and Ozagrel Sodium for Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage

Abstract: Fasudil hydrochloride is a new type of intracellular

Cited by 27 publications

References 23 publications

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

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

Fasudil, a Clinically Used ROCK Inhibitor, Stabilizes Rod Photoreceptor Synapses after Retinal Detachment

p120-catenin in cancer – mechanisms, models and opportunities for intervention

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