Safe and Efficient Drug Delivery System with Liposomes for Intrathecal Application of an Antivasospastic Drug, Fasudil

Ishida, Tatsuhiro; Takanashi, Y; Kojima, Hiroshi

doi:10.1248/bpb.29.397

Cited by 38 publications

(16 citation statements)

References 48 publications

(46 reference statements)

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“…It is reported that relatively higher doses of fasudil (14 -48 mg⅐kg Ϫ1 ⅐day Ϫ1 ) produce a blocking action against calcium entry (2, 23) as well as an inhibitory effect on protein kinase C (3,23). We did not examine the intracellular calcium levels or protein kinase C levels in this study.…”

Section: Discussionmentioning

confidence: 94%

Crucial role of Rho-nuclear factor-κB axis in angiotensin II-induced renal injury

Ozawa

Kobori²

2007

American Journal of Physiology-Renal Physiology

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This study was performed to determine the effectiveness of the Rho kinase inhibitor and NF-kappaB inhibitor in renal injury of ANG II-infused hypertensive rats. Male Sprague-Dawley rats, maintained on a normal diet, received either a sham operation (n = 7) or continuous ANG II infusion (120 ng/min) subcutaneously via minipumps. The ANG II-infused rats were further subdivided into three subgroups (n = 7 each) to receive one of the following treatments during the entire period: vehicle, Rho kinase inhibitor (fasudil; 3 mg.kg(-1).day(-1) ip), or NF-kappaB inhibitor (parthenolide; 1 mg.kg(-1).day(-1) ip). After 12 days of ANG II infusion, systolic blood pressure (BP; 208 +/- 7 vs. 136 +/- 3 mmHg), Rho kinase activity, NF-kappaB activity, renal ANG II contents (160 +/- 25 vs. 84 +/- 14 pg/g), monocytic chemotactic protein (MCP) 1 mRNA, interstitial macrophage infiltration, transforming growth factor-beta1 (TGF-beta1) mRNA, interstitial collagen-positive area, urinary protein excretion (43 +/- 6 vs. 11 +/- 2 mg/day), and urinary albumin excretion were significantly enhanced compared with the Sham group. While fasudil or parthenolide did not alter systolic BP (222 +/- and 190 +/- 21, respectively), both treatments completely blocked ANG II-induced enhancement of NF-kappaB activity, renal ANG II contents (103 +/- 11 and 116 +/- 21 pg/g, respectively), MCP1 mRNA, interstitial macrophage infiltration, TGF-beta1 mRNA, interstitial collagen-positive area, urinary protein excretion (28 +/- 6 and 23 +/- 3 mg/day, respectively), and urinary albumin excretion. Importantly, parthenolide did not alter ANG II-induced Rho kinase activation although fasudil abolished ANG II-induced Rho kinase activation. These data indicate that the Rho-NF-kappaB axis plays crucial roles in the development of ANG II-induced renal injury independently from BP regulation.

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Section: Discussionmentioning

confidence: 94%

Crucial role of Rho-nuclear factor-κB axis in angiotensin II-induced renal injury

Ozawa

Kobori²

2007

American Journal of Physiology-Renal Physiology

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“…Preliminary experiments revealed that the half-life of HA-1077 injected directly into the eye was less than 24 hrs (data not shown), indicating that a more sustained release would be necessary. To improve the bioavailability of HA-1077, we packaged it into liposomes using palmitoyloleoylphosphatidylcholine (POPC) and cholesterol with remote loading approaches [24], [25], [26]. This method of drug delivery has been shown to provide sustained release within the intra-ocular space over several weeks [25], [26], [27].…”

Section: Resultsmentioning

confidence: 99%

Intravitreal Administration of HA-1077, a ROCK Inhibitor, Improves Retinal Function in a Mouse Model of Huntington Disease

Yasumura

et al. 2013

PLoS ONE

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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.

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“…Liposomes are biocompatible and biodegradable drug carriers that have the potential to enhance the potency and reduce the toxicity of therapeutic agents (Lian & Ho 2001). However, conventional liposomes do not undergo significant transport through the BBB in the absence of vector-mediated drug delivery (Misra et al 2003;Ishida et al 2006). Furthermore, these liposomes are coated with serum proteins immediately after intravenous administration and are rapidly removed from the bloodstream and cleared by the cells of the reticuloendothelial system (RES; Siwak et al 2002;Sadzuka et al 2006).…”

Section: Systemic Drug Delivery Systemsmentioning

confidence: 99%

Biomaterials for the central nervous system

Zhong

Bellamkonda

2008

J. R. Soc. Interface.

217

163

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Biomaterials are widely used to help treat neurological disorders and/or improve functional recovery in the central nervous system (CNS). This article reviews the application of biomaterials in (i) shunting systems for hydrocephalus, (ii) cortical neural prosthetics, (iii) drug delivery in the CNS, (iv) hydrogel scaffolds for CNS repair, and (v) neural stem cell encapsulation for neurotrauma. The biological and material requirements for the biomaterials in these applications are discussed. The difficulties that the biomaterials might face in each application and the possible solutions are also reviewed in this article.

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Safe and Efficient Drug Delivery System with Liposomes for Intrathecal Application of an Antivasospastic Drug, Fasudil

Cited by 38 publications

References 48 publications

Crucial role of Rho-nuclear factor-κB axis in angiotensin II-induced renal injury

Crucial role of Rho-nuclear factor-κB axis in angiotensin II-induced renal injury

Intravitreal Administration of HA-1077, a ROCK Inhibitor, Improves Retinal Function in a Mouse Model of Huntington Disease

Biomaterials for the central nervous system

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