Combined Efficacy of Systemically Acting Diclofenac Sodium Patch and Alpha-2-Delta Calcium Channel Ligand in Chronic Low Back Pain: Subanalysis of a Phase III Study.

INTRODUCTION: Chronic low back pain often comprises mixed pain types and involves multiple factors. Therefore, we hypothesized that the systemic transdermal formulation of diclofenac sodium (DF systemic patch), which is effective for nociceptive pain, and an α2δ Ca2+ channel ligand, which is effective for neuropathic pain, would have additive effects in the treatment of chronic low back pain. METHODS: From among participants in a randomized, double-blind, placebo-controlled study of DF systemic patch (75 or 150 mg) applied once daily for 2 weeks in patients with chronic low back pain, we performed a subpopulation analysis of those who were concomitantly treated with an α2δ Ca2+ channel ligand during the study period. The efficacy endpoint was pain intensity score on a visual analog scale (VAS). RESULTS: The difference (95% confidence interval) in the least square mean pain VAS score between patients in the 150-mg combination group, who were treated with 150-mg DF systemic patch and an α2δ Ca2+ channel ligand (n = 11), and those in the non-combination group, who were treated with placebo patch and α2δ Ca2+ channel ligand (n = 22), was - 15.09 mm (- 26.45, - 3.73). Because the upper limit of the 95% confidence interval was less than zero, this result indicates that the pain VAS score improved more in the 150-mg combination group than in the non-combination group (placebo group). CONCLUSIONS: The combination of the DF systemic patch and an α2δ Ca2+ channel ligand may be more effective than α2δ Ca2+ channel ligand monotherapy for controlling chronic low back pain. TRIAL REGISTRATION NUMBERS: JPRN-JapicCTI-205134 and jRCT2080225040.

Long-term evaluation of the safety and efficacy of a novel 20% oxybutynin hydrochloride lotion for primary palmar hyperhidrosis: An open-label extension study.

The long-term safety and efficacy of 52-week application of oxybutynin hydrochloride 20% lotion (20% OL) for the treatment of primary palmar hyperhidrosis (PPHH) in Japanese patients aged ≥12 years were evaluated in an open-label extension (OLE) of a 4-week, randomized, double-blind (DB) study. The OLE included 114 patients who completed the DB study and wished to continue treatment and 12 new patients. In the safety analysis population (125 patients), the incidence of adverse events (AEs) and adverse drug reactions (ADRs) was 79.2% and 36.0%, respectively. Serious AEs were observed in two patients but were considered unrelated to the investigational drug. The incidence of AEs that led to study discontinuation was 1.6%. The incidence of application site AEs and ADRs was 35.2% and 26.4%, respectively. The severity of most events was mild. The incidence of anticholinergic AEs related to dry mouth was 3.2% for thirst and 0.8% for dry throat. The long-term efficacy of 20% OL was confirmed by a long-lasting reduction in sweat volume and improvement in the Hyperhidrosis Disease Severity Scale and Dermatology Life Quality Index. This study has several limitations: First the results may include some bias because most of the participants were from the prior DB study; second, the results may not be generalizable because only a few participants were in the age group most susceptible to PPHH (i.e., < 15 years old); and third, the study did not obtain safety information from treatment for more than 52 weeks, so this information must be collected in clinical practice in the future. No reduced therapeutic effect was observed in patients with PPHH in this study after 52-week application of 20% OL. Also, few patients experienced serious AEs or AEs that led to study treatment discontinuation.

A novel lotion formulation of 20% oxybutynin hydrochloride for the treatment of primary palmar hyperhidrosis: A randomized, placebo-controlled, double-blind, phase III study.

BACKGROUND: No previous controlled studies have been specifically designed or adequately powered to show the efficacy of topical oxybutynin for palmar hyperhidrosis by using quantitative measures. OBJECTIVE: To evaluate efficacy of 20% oxybutynin hydrochloride lotion (20% OL) in reducing palmar sweat volume in patients with primary palmar hyperhidrosis (PPHH). METHODS: In a randomized controlled trial, Japanese patients with PPHH aged 12 years and older received either 20% OL (n = 144) or placebo (n = 140) on both palms once daily for 4 weeks. Palmar sweat volume was measured by the ventilated capsule method. For the primary outcome, response was defined as a reduction of sweat volume of at least 50% from baseline. RESULTS: At week 4, the responder rate for sweat volume was significantly higher in the 20% OL arm than in the placebo arm (52.8% vs 24.3%, respectively; treatment difference, 28.5% [95% CI, 17.7% to 39.3%]; P < .001). No serious adverse events occurred, and no adverse events led to treatment discontinuation. LIMITATIONS: The treatment period was only 4 weeks. CONCLUSIONS: In patients with PPHH, 20% OL is superior to placebo in reducing palmar sweat volume.

Systemically Acting Diclofenac Sodium Patch for Control of Low Back Pain: A Randomized, Double-Blind, Placebo-Controlled Study in Japan.

INTRODUCTION: Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used for pain disorders such as low back pain and exist in multiple formulations; however, no systemically acting transdermal formulations are available for low back pain. Transdermal formulations can be safely administered even to patients with trouble swallowing or at risk of aspiration, and without regard to the effect of food on drug absorption. Unlike locally acting formulations, systemically acting transdermal formulations need not be applied at the target site, so dosing is simple and the burden is not on one area of the skin. A patch with the systemically acting NSAID diclofenac sodium is approved in Japan for treatment of cancer-related pain, and we hypothesized that it would be useful for controlling low back pain. METHODS: This randomized, double-blind, placebo-controlled study aimed to evaluate the efficacy and safety of diclofenac sodium patch in Japanese patients with low back pain. Eligible patients were randomized to receive diclofenac sodium patch 75 mg or 150 mg or placebo once daily for 2 weeks. The primary endpoint was pain intensity assessed on a visual analog scale (VAS). RESULTS: Primary analysis of the primary endpoint showed that both doses of the diclofenac sodium patch (150 mg and 75 mg) were superior to placebo in terms of absolute change from baseline in mean 3-day VAS score after 2 weeks' treatment; the mean difference between the active and placebo treatments in this variable was -5.67 [95% confidence interval (CI) -9.34 to -2.00] mm in the 150 mg group and -5.68 (95% CI -9.34 to -2.01) mm in the 75 mg group. Most adverse events were mild. No serious adverse events occurred. CONCLUSION: In Japanese patients, diclofenac sodium patch is effective for the relief of low back pain and is well tolerated. TRIAL REGISTRATION: JPRN number, JPRN-JapicCTI-205134.

A multicenter, randomized, double-blind, placebo-controlled, comparative study to evaluate the efficacy and safety of newly developed diclofenac patches in patients with cancer pain.

ABSTRACT: This phase III multicenter randomized double-blind placebo-controlled comparative study evaluated the efficacy and safety of diclofenac sodium patches for the treatment of cancer pain. The study consisted of a 2-week to 4-week open-label dose-titration phase and a 4-week double-blind phase. In the double-blind phase, patients who were expected to continue treatment of cancer pain with nonopioid analgesics alone were randomized to the diclofenac sodium patch or placebo group. Once-daily diclofenac sodium patches were started at 150 mg/day (2 patches) and could be increased up to 225 mg/day (3 patches). The primary efficacy endpoint was the time to insufficient analgesic response. Statistical analysis of the double-blind phase included data from 120 patients of the diclofenac sodium patch group and 118 patients of the placebo group. Time to insufficient analgesic response was significantly longer with diclofenac sodium patches than with placebo (P = 0.0016). The hazard ratio for insufficient response for diclofenac sodium patch vs placebo was 0.459 (95% confidence interval, 0.275-0.768). Regarding sleep quality during the double-blind phase, the proportion of patients with "very good sleep" or "good sleep" in the diclofenac sodium patch and placebo groups was 90.8% and 88.1% at the start of the double-blind phase and 81.4% and 78.6% at the final assessment, respectively. The incidence of adverse events was 60.8% (73/120) in the diclofenac sodium patch group and 60.2% (71/118) in the placebo group. Once-daily diclofenac sodium patches are effective in treating cancer pain and are well tolerated.

Suppression of nanosilica particle-induced inflammation by surface modification of the particles.

It has gradually become evident that nanomaterials, which are widely used in cosmetics, foods, and medicinal products, could induce substantial inflammation. However, the roles played by the physical characteristics of nanomaterials in inflammatory responses have not been elucidated. Here, we examined how particle size and surface modification influenced the inflammatory effects of nanosilica particles, and we investigated the mechanisms by which the particles induced inflammation. We compared the inflammatory effects of silica particles with diameters of 30-1,000 nm in vitro and in vivo. In macrophages in vitro, 30- and 70-nm nanosilica particles (nSP30 and nSP70) induced higher production of tumor necrosis factor-α (TNFα) than did larger particles. In addition, intraperitoneal injection of nSP30 and nSP70 induced stronger inflammatory responses involving cytokine production than did larger particles in mice. nSP70-induced TNFα production in macrophage depended on the production of reactive oxygen species and the activation of mitogen-activated protein kinases (MAPKs). Furthermore, nSP70-induced inflammatory responses were dramatically suppressed by surface modification of the particles with carboxyl groups in vitro and in vivo; the mechanism of the suppression involved reduction in MAPK activation. These results provide basic information that will be useful for the development of safe nanomaterials.

The effect of surface modification of amorphous silica particles on NLRP3 inflammasome mediated IL-1beta production, ROS production and endosomal rupture.

Although amorphous silica particles (SPs) are widely used in cosmetics, foods and medicinal products, it has gradually become evident that SPs can induce substantial inflammation accompanied by interleukin-1beta (IL-1beta) production. Here, to develop safe forms of SPs, we examined the mechanisms of SP-induced inflammation and the relationship between particle characteristics and biological responses. We compared IL-1beta production levels in THP-1 human macrophage like cells in response to unmodified SP of various diameters (30- to 1000-nm) and demonstrated that unmodified microsized 1000-nm SP (mSP1000) induced higher levels of IL-1beta production than did smaller unmodified SPs. Furthermore, we found that unmodified mSP1000-induced IL-1beta production was depended on the sequence of reactive oxygen species (ROS) production, endosomal rupture, and subsequent activation of pro-inflammatory complex NLRP3 inflammasome. In addition, we compared IL-1beta production levels in THP-1 cells treated with mSP1000s modified with a functional group (-COOH, -NH(2), -SO(3)H, -CHO). Although unmodified and surface-modified mSP1000s were taken up with similar frequencies equally into the THP-1 cells, surface modification of mSP1000 dramatically suppressed IL-1beta production by reducing ROS production. Our results reveal a part of NLRP3 activation pathway and provide basic information that should help to create safe and effective forms of SPs.

Creation of a LIGHT mutant with the capacity to evade the decoy receptor for cancer therapy.

The cytokine LIGHT activates various anti-tumor functions through its two receptors, lymphotoxin beta receptor (LTbetaR) and herpes virus entry mediator (HVEM), and is expected to be a promising candidate for cancer therapy. However, LIGHT is also trapped by decoy receptor 3 (DcR3), which is highly expressed in various tumors. Here, we used phage display technique to create LIGHT mutants that specifically bind LTbetaR and HVEM, and is not trapped by DcR3 for optimized cancer therapy. We constructed phage library displaying structural variants of LIGHT with randomized amino acid residues. After the affinity panning, we created 6 clones of LIGHT mutants as candidates for DcR3-evading LIGHT. Analysis of binding affinities showed that all candidates had 10-fold lower affinities for DcR3 than wild-type LIGHT, while 5 of the 6 clones had almost the same affinity for LTbetaR and HVEM. Furthermore, analysis of detailed binding kinetics showed that lower affinity for DcR3 is dependent on their faster off-rate. Further, we showed that the LIGHT mutant had almost the same cytotoxicity via LTbetaR, and had 62-fold higher DcR3-evading capacity compared to the wild type. Our data provide valuable information for construction of more functional LIGHT mutants that might be powerful tools for cancer therapy.

Creation of a lysine-deficient LIGHT mutant with the capacity for site-specific PEGylation and low affinity for a decoy receptor.

The cytokine LIGHT is a promising candidate for cancer therapy. However, the therapeutic effect of LIGHT as a systemic anticancer agent is currently insufficient because of its instability and its binding to nonfunctional soluble decoy receptor 3 (DcR3), which is overexpressed in various tumors. Modification of proteins with polyethylene glycol (PEGylation) can improve their in vivo stability, but PEGylation may occur randomly at all lysine residues and the NH(2)-terminus; therefore, PEGylated proteins are generally heterogeneous and have decreased bioactivity. In this study, we attempted to create a lysine-deficient LIGHT mutant that could be PEGylated site-specifically and would have lower affinity for DcR3. We prepared phage libraries expressing LIGHT mutants in which all the lysine residues were replaced with other amino acids. A lysine-deficient LIGHT mutant [mLIGHT-Lys(-)] was isolated by panning against lymphotoxin beta receptor (LTbetaR). mLIGHT-Lys(-) could be site-specifically PEGylated at its NH(2)-terminus, yielding molecular uniformity and in vitro bioactivity equal to that of non-PEGylated, wild-type LIGHT. Furthermore, mLIGHT-Lys(-) was not trapped by the nonfunctional DcR3, despite binding to its functional receptors. These results suggest that mLIGHT-Lys(-) might be a useful candidate for cancer therapy.

LIGHT protein suppresses tumor growth by augmentation of immune response.

The tumor necrosis factor (TNF) superfamily member LIGHT has potent anti-tumor activities through activation of the immune response, and it is a promising candidate for use in cancer immunotherapy. However, there are no reports of the anti-tumor effects of LIGHT protein in vivo because of the lack of easy, efficient methods of manufacturing this protein. Here, we developed a method of manufacturing recombinant LIGHT protein using Escherichia coli through refolding of inclusion bodies; we then evaluated the anti-tumor activity of the protein. LIGHT protein expressed in E. coli showed the same biological activities and binding affinities to its receptors as did LIGHT expressed in mammalian cells. In addition, intratumoral injection of LIGHT significantly suppressed tumor growth, with augmentation of antigen-specific IFN-gamma-producing cells in the regional lymph nodes and spleen. These results indicate that LIGHT protein efficiently evokes the systemic tumor-specific immune response, and thus induces tumor suppression.