A Colon-Targeted Prodrug of Riluzole Improves Therapeutic Effectiveness and Safety upon Drug Repositioning of Riluzole to an Anti-Colitic Drug

Riluzole (RLZ) is a neuroprotective drug indicated for amyotrophic lateral sclerosis. To examine the feasibility of RLZ for repositioning as an anti-inflammatory bowel disease (IBD) drug, RLZ (2, 5, and 10 mg/kg) was administered orally to rats with colitis induced by 2,4-dinitrobenzenesulfonic acid. Oral RLZ was effective against rat colitis in a dose-dependent manner, which was statistically significant at doses over 5 mg/kg. To address safety issues upon repositioning and further improve anti-colitic effectiveness, RLZ was coupled with salicylic acid (SA) via an azo-bond to yield RLZ-azo-SA (RAS) for the targeted colonic delivery of RLZ. Upon oral gavage, RAS (oral RAS) was efficiently delivered to and activated to RLZ in the large intestine, and systemic absorption of RLZ was substantially reduced. Oral RAS ameliorated colonic damage and inflammation in rat colitis and was more effective than oral RLZ and sulfasalazine, a current anti-IBD drug. Moreover, oral RAS potently inhibited glycogen synthase kinase 3β (GSK3β) in the inflamed distal colon, leading to the suppression of NFκB activity and an increase in the level of the anti-inflammatory cytokine interleukin-10. Taken together, RAS, which enables RLZ to be delivered to and inhibit GSK3β in the inflamed colon, may facilitate repositioning of RLZ as an anti-IBD drug

Novel reverse electrodialysis-driven iontophoretic system for topical and transdermal delivery of poorly permeable therapeutic agents

<p>Topical and transdermal drug delivery has great potential in non-invasive and non-oral administration of poorly bioavailable therapeutic agents. However, due to the barrier function of the stratum corneum, the drugs that can be clinically feasible candidates for topical and transdermal delivery have been limited to small-sized lipophilic molecules. Previously, we fabricated a novel iontophoretic system using reverse electrodialysis (RED) technology (RED system). However, no study has demonstrated its utility in topical and/or transdermal delivery of poorly permeable therapeutic agents. In this study, we report the topical delivery of fluorescein isothiocyanate (FITC)–hyaluronic acid (FITC–HA) and vitamin C and the transdermal delivery of lopinavir using our newly developed RED system in the <i>in vitro</i> hairless mouse skin and <i>in vivo</i> Sprague–Dawley rat models. The RED system significantly enhanced the efficiency of topical HA and vitamin C and transdermal lopinavir delivery. Moreover, the efficiency and safety of transdermal delivery using the RED system were comparable with those of a commercial ketoprofen patch formulation. Thus, the RED system can be a potential topical and transdermal delivery system for various poorly bioavailable pharmaceuticals including HA, vitamin C, and lopinavir.</p

Anti-inflammatory effect of <i>Allium hookeri</i> on carrageenan-induced air pouch mouse model

<div><p>Inflammation is a commonly observed immune reaction, and rheumatoid arthritis is a particularly severe inflammatory disease. In this study, we used an air pouch mouse model to evaluate the anti-inflammatory potential of <i>Allium hookeri</i>, which has both been used as a culinary material and a traditional medicine in south-eastern Asia for many years. <i>Allium hookeri</i> suppressed typical symptoms of inflammation, such as condensation of the air pouch membrane, and inhibited the expression of several inducible proinflammatory cytokines such as IL-1β, IL-6, IL-13, and TNF-α. In order to determine the molecules modulating the inflammatory effect of carrageenan treatment, the components in <i>Allium hookeri</i> were analyzed by GC-MS, and linoleic acid, which have anti-inflammatory effect, was detected. From the results, we concluded that the anti-inflammatory effect of <i>Allium hookeri</i> might be attributed to linoleic acid, which could be promising candidates for anti-inflammatory drugs that have no adverse effects.</p></div

Operation parameters for the GC/MS.

<p>[1] HP Agilent GC:7890A MS:5975C.</p

<i>Allium hookeri</i> suppresses the histopathological changes which are induced by carrageenan treatment.

<p>a, control; b, 1% carrageenan treated group; c, 5 mg/kg indomethacin treated group; d, 30 mg/kg <i>A</i>. <i>hookeri</i> treated group; e, 300 mg/kg <i>A</i>. <i>hookeri</i> treated group, AM, air pouch membrane; Scare bar, 200 μm.</p

Analyzed compounds from <i>Allium hookeri</i> by GC/MS.

<p>Analyzed compounds from <i>Allium hookeri</i> by GC/MS.</p

<i>Allium hookeri</i> suppresses the inflammatory cells proliferation in carrageenan-induced air pouch model.

<p>Animals were orally administered with different doses of <i>A</i>. <i>hookeri</i> 24 h and 1 h prior to carrageenan (1%) injection into the air pouch. The results are presented as mean ± S.D. (n = 9) of total leukocytes (× 10³ cells/mL). * vs. control, p < 0.05; ** vs. control, p < 0.001; $ vs. 5 mg/kg indomethacin treated group, p < 0.05; # vs. carrageenan treated group, p < 0.05; & vs. 30 mg/kg <i>A</i>. <i>hookeri</i> treated group, p < 0.05.</p

<i>Allium hookeri</i> suppresses the expression of several inflammation induction markers in the skin which are upregulated by carrageenan treatment.

<p>A is the photo of IL-1β expression, B is the photo of IL-6 expression, C is the photo of IL-13 expression, and D is the photo of TNF-α expression in the skin. a, control group; b, 1% carrageenan treated group; c, 5 mg/kg indomethacin treated group; d, 30 mg/kg <i>A</i>. <i>hookeri</i> treated group; e, 300 mg/kg <i>A</i>. <i>hookeri</i> treated group. Scare bar, 200 μm.</p

LC/ESI MS/MS of trypsin/Glu-C digests of R27T and Rebif.

<p>(A) Extraction ion chromatogram at m/z 204 and 366 for product ion spectra at 21 min and 46 min, respectively. Amino acid sequencing of deglycosylated C3 and C13 peptides by LC/ESI MS/MS. (B) Deglycosylated C3 peptide MS spectrum and fragmentation information for R27T (Lot: 12104DS01 and 12103DS01) and Rebif. (C) MS spectrum of the deglycosylated C13 peptide and fragmentation information for R27T (Lot: 12104DS01 and 12103DS01) and Rebif.</p

Glycoengineering of Interferon-β 1a Improves Its Biophysical and Pharmacokinetic Properties

<div><p>The purpose of this study was to develop a biobetter version of recombinant human interferon-β 1a (rhIFN-β 1a) to improve its biophysical properties, such as aggregation, production and stability, and pharmacokinetic properties without jeopardizing its activity. To achieve this, we introduced additional glycosylation into rhIFN-β 1a via site-directed mutagenesis. Glycoengineering of rhIFN-β 1a resulted in a new molecular entity, termed R27T, which was defined as a rhIFN-β mutein with two N-glycosylation sites at 80^th (original site) and at an additional 25^th amino acid due to a mutation of Thr for Arg at position 27^th of rhIFN-β 1a. Glycoengineering had no effect on rhIFN-β ligand-receptor binding, as no loss of specific activity was observed. R27T showed improved stability and had a reduced propensity for aggregation and an increased half-life. Therefore, hyperglycosylated rhIFN-β could be a biobetter version of rhIFN-β 1a with a potential for use as a drug against multiple sclerosis.</p></div