Prostaglandin I2 (PGI2) and its analogues (such as beraprost sodium, BPS) are beneficial for the treatment of pulmonary arterial hypertension (PAH). The encapsulation of BPS in nanoparticles to provide sustained release and targeting abilities would improve both the therapeutic effect of BPS on PAH and the quality of life of patients treated with this drug.BPS was encapsulated into nanoparticles prepared from a poly(lactic acid) homopolymer and monomethoxy poly(ethyleneglycol)–poly(lactide) block copolymer. The accumulation of nanoparticles in damaged pulmonary arteries was examined using fluorescence-emitting rhodamine S-encapsulated nanoparticles. The monocrotaline-induced PAH rat model and the hypoxia-induced mouse model were used to examine the pharmacological activity of BPS-encapsulated nanoparticles.A nanoparticle, named BPS-NP, was selected among various types of BPS-encapsulated nanoparticles tested; this was based on the sustained release profile in vitro and blood clearance profile in vivo. Fluorescence-emitting rhodamine S-encapsulated nanoparticles were prepared in a similar manner to that of BPS-NP, and showed accumulation and prolonged residence in monocrotaline-damaged pulmonary peripheral arteries. Intravenous administration of BPS-NP (once per week, 20 μg/kg) protected against monocrotaline-induced pulmonary arterial remodeling and right ventricular hypertrophy. The extent of this protection was similar to that observed with oral administration (once per day, 100 μg/kg) of BPS alone. The once per week intravenous administration of BPS-NP (20 μg/kg) also exhibited an ameliorative effect on hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy.The beneficial effects of BPS-NP on PAH animal models seem to be mediated by its sustained release and tissue targeting profiles. BPS-NP may be useful for the treatment of PAH patients due to reduced dosages and frequency of BPS administration.

Non-steroidal anti-inflammatory drugs (NSAIDs) achieve their anti-inflammatory effect by inhibiting cyclooxygenase activity. We previously suggested that in addition to cyclooxygenase-inhibition at the gastric mucosa, NSAID-induced gastric mucosal cell death is required for the formation of NSAID-induced gastric lesions in vivo. We showed that celecoxib exhibited the most potent membrane permeabilizing activity among the NSAIDs tested. In contrast, we have found that the NSAID rofecoxib has very weak membrane permeabilizing activity. To understand the membrane permeabilizing activity of coxibs in terms of their structure–activity relationship, we separated the structures of celecoxib and rofecoxib into three parts, synthesized hybrid compounds by substitution of each of the parts, and examined the membrane permeabilizing activities of these hybrids. The results suggest that the sulfonamidophenyl subgroup of celecoxib or the methanesulfonylphenyl subgroup of rofecoxib is important for their potent or weak membrane permeabilizing activity, respectively. These findings provide important information for design and synthesis of new coxibs with lower membrane permeabilizing activity.

We previously reported that 2-fluoroloxoprofen has lower gastric ulcerogenic activity than loxoprofen, a nonsteroidal anti-inflammatory drug (NSAID) without selectivity for COX-2. We synthesized derivatives of 2-fluoroloxoprofen and studied their properties. Compared to 2-fluoroloxoprofen, one derivative, 11a, exhibited higher anti-inflammatory activity and an equivalent ulcerogenic effect. These results suggest that 11a could be therapeutically beneficial for use as an NSAID.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the author.The article is a substantial duplicate of a paper that has already been published by the same author in Curr Pharm Des, 16 (2010) 1190–1196, http://dx.doi.org/10.2174/138161210790945986.

•We here searched for HSP70-inducers from a library of herbal extracts that have already been approved as quasi-pharmaceutical products in Japan.•We selected an ethanol extract of Arnica montana and purified an HSP70-inducer, AM-2 (helenalin 2-methylbutyrate).•Pre-treatment of cells with AM-2 or Arnica montana extract decreased melanin production.•These results suggest that AM-2 and Arnica montana extract could be beneficial for use in hypopigmenting cosmetics as a consequence of their stimulatory effects on HSP70 expression.BackgroundThe expression of heat shock proteins (HSPs), particularly HSP70, is receiving considerable attention in the field of cosmetics, particularly given our recent report that ultraviolet-induced melanin production, skin damage and wrinkle formation were all suppressed in transgenic mice expressing HSP70.ObjectiveIn the present study, we searched for HSP70-inducers from a library of herbal extracts that have already been approved as quasi-pharmaceutical products in Japan. We selected an ethanol extract of Arnica montana (A. montana), based on its high HSP70-inducing activity and low cytotoxicity.MethodsCell viability was determined by MTT method and expression of HPS70 was monitored by immunoblotting analysis.ResultsFrom the extract, we purified and identified eight sesquiterpene lactones (AM1–8) as HSP70-inducers, among which AM-2 (helenalin 2-methylbutyrate) was selected due to its good HSP70-inducing properties and low cytotoxicity. Treatment of cultured mouse melanoma cells with AM-2 or A. montana extract up-regulated the expression of HSP70 in a dose-dependent manner. This treatment also activated heat shock factor-1, a transcription factor for hsp genes. Furthermore, pre-treatment of cells with AM-2 or A. montana extract decreased melanin production and expression and activity of tyrosinase.ConclusionThese results suggest that AM-2 and A. montana extract could be beneficial for use in hypopigmenting cosmetics as a consequence of their stimulatory effects on HSP70 expression.

UV-induced wrinkle formation owing to the degeneration of the extracellular matrix (ECM) is a major dermatological problem in which abnormal activation of matrix metalloproteinases (MMPs) and elastases have important roles. Heat shock protein 70 (HSP70) has cytoprotective and anti-inflammatory activities. In this study, we examined the effect of HSP70 expression on UV-induced wrinkle formation. Mild heat treatment (exposure to heated water at 42 °C) of the dorsal skin of hairless mice induced the expression of HSP70. The long-term repeated exposure to UV induced epidermal hyperplasia, decreased skin elasticity, degeneration of ECM, and wrinkle formation, which could be suppressed in mice concomitantly subjected to this heat treatment. The UV-induced epidermal hyperplasia, decreased skin elasticity, and degeneration of ECM were less apparent in transgenic mice expressing HSP70 than in wild-type mice. UV-induced fibroblast cell death, infiltration of inflammatory cells, and activation of MMPs and elastase in the skin were also suppressed in the transgenic mice. This study provides evidence for an inhibitory effect of HSP70 on UV-induced wrinkle formation. The results suggest that this effect is mediated by various properties of HSP70, including its cytoprotective and anti-inflammatory activities. We propose that HSP70 inducers used in a clinical context could prove beneficial for the prevention of UV-induced wrinkle formation.

We recently reported that, compared to loxoprofen (LOX, an non-steroidal anti-inflammatory drug), the LOX derivative fluoro-loxoprofen (F-LOX) is less ulcerogenic but has similar anti-inflammatory activity. Our previous in vitro studies suggested that both LOX and F-LOX are pro-drugs, the active metabolites of which are their trans-alcohol forms. In this study, we compared the pharmacokinetics of F-LOX and LOX in rats. Overall, the pharmacokinetic characteristics of F-LOX, including the formation of metabolites in vivo and in vitro, were comparable to those of LOX. However, F-LOX disappeared from the plasma more rapidly than LOX, which could potentially explain its lower ulcerogenicity. However, we showed that F-LOX produced fewer gastric lesions than LOX, even when a higher plasma concentration of F-LOX was maintained. Similar to LOX, F-LOX was readily metabolized to its trans- and cis-alcohol forms, with a higher level of the trans-alcohol form being observed after oral or intravenous administration of the drug. The preferential formation of the trans-alcohol form was also observed after incubation of F-LOX with rat liver homogenates in vitro. These results suggest that, similar to LOX, F-LOX acts as a pro-drug and that there is a metabolic system that selectively produces its active metabolite.