The efficacy and safety of a fixed-dose combination of apocynin and paeonol, APPA, in symptomatic knee OA: A double-blind, randomized, placebo-controlled, clinical trial.

OBJECTIVE: Apocynin (AP) and paeonol (PA) are low molecular weight phenolic compounds with a broad array of anti-inflammatory and immunoregulatory effects. This study assessed of a fixed-dose combination of APPA in people with symptomatic knee osteoarthritis (OA). METHODS: A multi-center, randomized, placebo-controlled, double-blind phase 2a trial enrolled participants with radiographic knee OA (Kellgren-Lawrence, KL, grades 2-3) and pain ≥40/100 on WOMAC pain subscale, and evaluated the efficacy and safety of oral APPA over a 28-day period. APPA 800 mg or matching placebo was administered twice daily in a 1:1 ratio. Post-hoc analyses explored the response to APPA in sub-groups with more severe pain and structural severity. RESULTS: The two groups were comparable at baseline; 152 subjects were enrolled and 148 completed the trial. There was no statistically significant difference between groups with respect to the primary outcome, WOMAC pain (mean difference between groups was -0.89, 95% CI: -5.62, 3.84, p = 0.71), nor WOMAC function or WOMAC total. However, predefined subgroup analyses of subjects with symptoms compatible with nociplastic/neuropathic pain features showed a statistically significant effect of APPA compared to placebo. Adverse events (mainly gastrointestinal) were mild to moderate. CONCLUSION: Treatment with APPA 800 mg twice daily for 28 days in subjects with symptomatic knee OA was not associated with significant symptom improvement compared to placebo. The treatment was well-tolerated and safe. While the study was not powered for such analysis, pre-planned subgroup analyses showed a significant effect of APPA in subjects with nociplastic pain/severe OA, indicating that further research in the effects of APPA in appropriate patients is warranted.

Sensitization properties of acetophenone azine, a new skin sensitizer identified in textile.

BACKGROUND: Acetophenone azine (CAS no. 729-43-1) present in sports equipment (shoes, socks and shin pads) has been suspected to induce skin allergies. Twelve case reports of allergy in children and adults from Europe and North America were published between 2016 and 2021. OBJECTIVES: The objective of this study was to confirm that acetophenone azine is indeed a skin sensitizer based on in vitro/ in vivo testings derived from the Adverse Outcome Pathway (AOP) built for skin sensitization by OECD in 2012. METHODS: Acetophenone azine was tested in vitro according to the human cell line activation test (h-CLAT) and the ARE-Nrf2 Luciferase Test (KeratinoSens) and in vivo using the Local Lymph Nodes Assay (LLNA). RESULTS: Both the h-CLAT and the KeratinoSens were positive whereas the LLNA performed at 5, 2.5 and 1% (wt/vol) of acetophenone azine, was negative. CONCLUSION: Based on these results, acetophenone azine was considered as a skin sensitizer. This was recently confirmed by its classification under the CLP regulation.

Anti-inflammatory effects of B vitamins protect against tau hyperphosphorylation and cognitive impairment induced by 1,2 diacetyl benzene: An in vitro and in silico study.

1,2 diacetyl benzene (DAB) penetrates the blood-brain barrier, causing neuroinflammation, tau hyperphosphorylation, and cognitive impairment. Converging evidence supports the anti-inflammatory effects of B vitamins on cognitive impairment, but the effects of B vitamins on cognitive impairment induced by DAB remain unclear. Here, we investigated the anti-inflammatory properties of B vitamins in DAB-stimulated human neuroblastoma SH-SY5Y cells. In this in-silico analysis, we investigated the genes, transcription factors, miRNAs, and sponges linked with DAB, B vitamins and the pathogenesis of cognitive impairment. We found vitamins B1, B2, and B3 had anti-inflammatory properties in DAB-stimulated SH-SY5Y cells, possibly via inhibiting NF-κB activation. Furthermore, vitamins B1, B2, and B3 inhibited GSK-3ß, ß-amyloid, and tau hyperphosphorylation in SH-SY5Y cells. These vitamins can also modulate genes induced by DAB (IL1B, IL6, IL10, iNOS, COX2, NFκB, GSK3B, TNF, and APP) in SH-SY5Y cells. In silico analyses, inflammatory response related pathways, "Alzheimer's disease", "pathways of neurodegeneration-multiple disease", and "prolactin signaling pathway", were highlighted. Additionally, we explored a network-based approach to identify key genes, transcription factors, miRNAs, and pathways in cognitive impairment. The transcription factors NFKB2 and BATF3 were shown to be the most important in regulating genes. We also found eight significant miRNAs related to cognitive impairment, and these miRNAs were also validated by qPCR. Finally, we developed and tested in silico miRNA sponge sequences for these miRNAs.

Acetophenone Azine: The 2021 American Contact Dermatitis Society Allergen of the Year.

The American Contact Dermatitis Society chose acetophenone azine (AA) as the 2021 Allergen of the Year. Acetophenone azine is an emerging contact allergen that often is associated with the use of sports equipment and footwear. The pattern of dermatitis initially starts locally at the site of contact but can develop into a generalized dermatitis. Strong suspicion is necessary to diagnose AA allergy, and patch testing should be completed with AA and to potentially relevant sports equipment and/or shoes. Acetophenone azine is not yet available as a commercial patch-test preparation, but the optimal concentration is 0.1% in acetone or petrolatum. This column serves as an introduction to AA as an emerging allergen and highlights diagnosis, management, and patch testing for AA contact allergy.

Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase IIb study.

BACKGROUND & AIMS: MSDC-0602K is a novel insulin sensitizer designed to preferentially target the mitochondrial pyruvate carrier while minimizing direct binding to the transcriptional factor PPARγ. Herein, we aimed to assess the efficacy and safety of MSDC-0602K in patients with non-alcoholic steatohepatitis. METHODS: Patients with biopsy-confirmed NASH and fibrosis (F1-F3) were randomized to daily oral placebo, or 1 of 3 MSDC-0602K doses in a 52-week double-blind study. The primary efficacy endpoint was hepatic histological improvement of ≥2 points in non-alcoholic fatty liver disease activity score (NAS) with a ≥1-point reduction in either ballooning or lobular inflammation and no increase in fibrosis stage at 12 months. Secondary endpoints included NAS improvement without worsening fibrosis, NASH resolution, and fibrosis reduction. Exploratory endpoints included changes in insulin sensitivity, liver injury and liver fibrosis markers. RESULTS: Patients were randomly assigned to placebo (n = 94), or 62.5 mg (n = 99), 125 mg (n = 98), or 250 mg (n = 101) of MSDC-0602K. At baseline, glycated hemoglobin was 6.4 ±â€¯1.0%, 61.5% of patients had fibrosis F2/F3 and the average NAS was 5.3. The primary endpoint was reached in 29.7%, 29.8%, 32.9% and 39.5% of patients in the placebo, 62.5 mg, 125 mg and 250 mg dose arms, respectively, with adjusted odds ratios relative to placebo of 0.89 (95% CI 0.44-1.81), 1.22 (95% CI 0.60-2.48), and 1.64 (95% CI 0.83-3.27). The 2 highest doses of MSDC-0602K led to significant reductions in glucose, glycated hemoglobin, insulin, liver enzymes and NAS compared to placebo. The incidence of hypoglycemia and PPARγ-agonist-associated events such as edema and fractures were similar in the placebo and MSDC-0602K groups. CONCLUSIONS: MSDC-0602K did not demonstrate statistically significant effects on primary and secondary liver histology endpoints. However, effects on non-invasive measures of liver cell injury and glucose metabolism support further exploration of MSDC-0602K's safety and potential efficacy in patients with type 2 diabetes and liver injury. [ClinicalTrials.gov Identifier: NCT02784444]. LAY SUMMARY: First-generation insulin sensitizers are used to treat type 2 diabetes, but are associated with side effects including edema, bone fractures, and hypoglycemia. MSDC-0602K is a second-generation insulin sensitizer designed to reduce these side effects. We hypothesized that insulin sensitization could improve non-alcoholic steatohepatitis. In the current study of patients with non-alcoholic steatohepatitis, MSDC-0602K did not demonstrate significant effects on liver histology with the biopsy techniques used. However, useful information was gained for the design of future studies and MSDC-0602K significantly decreased fasting glucose, insulin, glycated hemoglobin, and markers of liver injury without dose-limiting side effects.

Allergic Contact Dermatitis to Shin Pads in a Hockey Player: Acetophenone Is an Emerging Allergen.

Acetophenone azine (AA) has recently been identified as a new allergen in shin pads and sports shoes. We report the case of a boy with allergic contact dermatitis of the shins caused by AA present in his shin pads. High-performance liquid chromatography of samples of shin pads was performed to help identify potential contact allergens. Patch tests revealed strongly positive reactions to pieces of his shin pads and to AA down to a concentration of 0.001% in acetone. To our knowledge, this is the first reported case of allergic contact dermatitis to AA in the United Kingdom. Here we recommend the optimal concentration of AA for patch testing at 0.1% in acetone and summarize previous relevant published cases.

Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1.

MACC1 (Metastasis Associated in Colon Cancer 1) is a key driver and prognostic biomarker for cancer progression and metastasis in a large variety of solid tumor types, particularly colorectal cancer (CRC). However, no MACC1 inhibitors have been identified yet. Therefore, we aimed to target MACC1 expression using a luciferase reporter-based high-throughput screening with the ChemBioNet library of more than 30,000 compounds. The small molecules lovastatin and rottlerin emerged as the most potent MACC1 transcriptional inhibitors. They remarkably inhibited MACC1 promoter activity and expression, resulting in reduced cell motility. Lovastatin impaired the binding of the transcription factors c-Jun and Sp1 to the MACC1 promoter, thereby inhibiting MACC1 transcription. Most importantly, in CRC-xenografted mice, lovastatin and rottlerin restricted MACC1 expression and liver metastasis. This is-to the best of our knowledge-the first identification of inhibitors restricting cancer progression and metastasis via the novel target MACC1. This drug repositioning might be of therapeutic value for CRC patients.

Pharmacological inhibition of NADPH oxidase protects against cisplatin induced nephrotoxicity in mice by two step mechanism.

BACKGROUND: Cisplatin induced nephrotoxicity is primarily caused by ROS (Reactive Oxygen Species) induced proximal tubular cell death. NADPH oxidase is major source of ROS production by cisplatin. Here, we reported that pharmacological inhibition of NADPH oxidase by acetovanillone (obtained from medicinal herb Picrorhiza kurroa) led to reduced cisplatin nephrotoxicity in mice. METHODS: In this study we used various molecular biology and biochemistry methods a clinically relevant model of nephropathy, induced by an important chemotherapeutic drug cisplatin. RESULTS: Cisplatin-induced nephrotoxicity was evident by histological damage from loss of the tubular structure. The damage was also marked by the increase in blood urea nitrogen, creatinine, protein nitration as well as cell death markers such as caspase 3/7 activity and DNA fragmentation. Tubular cell death by cisplatin led to pro-inflammatory response by production of TNFα and IL1ß followed by leukocyte/neutrophil infiltration which resulted in new wave of ROS involving more NADPH oxidases. Cisplatin-induced markers of kidney damage such as oxidative stress, cell death, inflammatory cytokine production and nephrotoxicity were attenuated by acetovanillone. In addition to that, acetovanillone enhanced cancer cell killing efficacy of cisplatin. CONCLUSION: Thus, pharmacological inhibition of NADPH oxidase can be protective for cisplatin-induced nephrotoxicity in mice.

A double-blind, randomized, placebo and active-controlled study of nebicapone for the treatment of motor fluctuations in Parkinson's disease.

To determine the efficacy, safety and tolerability of nebicapone, a new catechol-O-methyltransferase inhibitor for the treatment of motor fluctuations in Parkinson's disease (PD), we conducted a multicenter, randomized, 8-week double-blind, placebo- and active-controlled, parallel-group study comparing nebicapone 50 mg, 100 mg, or 150 mg, entacapone 200 mg (active control) or placebo administered concomitantly with levodopa/carbidopa or levodopa/benserazide. Two hundred and fifty-two PD patients with motor fluctuations treated with levodopa/carbidopa or levodopa/benserazide (4-8 daily doses) were enrolled and 250 patients were eligible for intention-to-treat (ITT) analysis on the basis of having at least one efficacy assessment. The primary endpoint was 8-week change from baseline in absolute "Off" time duration noted in self-scoring diaries. At 8 weeks of treatment the mean daily "Off" time decreased significantly compared to placebo for nebicapone 150 mg (-106 min; 95%CI: -192; -21) and entacapone 200 mg (-81 min; 95%CI: -142; -19). The decrease in "Off" time with nebicapone 50 mg or 100 mg did not reach statistical significance. Treatment-emergent adverse events were reported by 32% to 49% of patients in any treatment group, with no observed dose relationship in the nebicapone groups. Clinically relevant elevations in aspartate transaminase (AST) and/or alanine transaminase (ALT) were observed in 4 of 46 patients with the nebicapone 150 mg dose. The results of this study show that nebicapone 150 mg is efficacious for the treatment of motor fluctuations in PD patients. However, the risk of increasing liver transaminases and its clinically relevance deserves further evaluation.

Apocynin decreases hydrogen peroxide and nitrate concentrations in exhaled breath in healthy subjects.

The imbalance between reactive oxygen species (ROS) synthesis and antioxidants might be involved in the pathogenesis of many inflammatory diseases. NADPH oxidase, an enzyme responsible for ROS production, may represent an attractive therapeutic target to inhibit, for the treatment of these diseases. Apocynin is an inhibitor of activation of NADPH oxidase complex present in the inflammatory cells. In double blind, placebo-controlled, cross-over study, we investigated the effect of nebulized apocynin on ROS synthesis in 10 nonsmoking healthy volunteers. Apocynin (6ml of 0.5mg/ml) was administered by nebulization and its effects on H(2)O(2), NO(2)(-) and NO(3)(-) generation were assessed after 30, 60 and 120min by collecting exhaled breath condensate (EBC) samples using an EcoScreen analyzer. Additionally, respiratory parameters have been evaluated, utilizing spirometry and DLCO. We also analyzed peripheral blood differential counts and NO(2)(-) serum level, cough scale control and blood pressure as safety parameters. Apocynin caused reduction of H(2)O(2) concentration in EBC as compared to placebo, after 60min. of inhalation (0.18microM vs. 0.31microM, p<0.05) as well as after 120min. (0.2microM vs. 0.31microM, p<0.05). Similarly, apocynin significantly decreased concentration of NO(3)(-) as compared to placebo, after 60 and 120min. (6.8microM vs. 14.4microM and 6.5microM vs. 14.9microM respectively, p<0.05). Apocynin was well tolerated and no adverse events have been observed throughout the study. Thus, as apocynin significantly influence ROS concentration, it might have also antiinflammatory properties. As it is safe, it may have a potential to become a drug in airway inflammatory diseases treatment.

The role of the methoxyphenol apocynin, a vascular NADPH oxidase inhibitor, as a chemopreventative agent in the potential treatment of cardiovascular diseases.

Oxidative stress has been linked to the origin and progression of cardiovascular diseases. Nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase is a multi-component, NADPH-dependent enzyme that generates superoxide anion in the presence of molecular oxygen. The enzyme has been identified and characterized in all 3 vascular wall cell types and represents the major source of reactive oxygen species (ROS) production in the vascular wall. Inhibition of NADPH oxidase activation appears to suppress the sequence of cellular events that leads to a variety of cardiovascular diseases, including atherosclerosis. The naturally occurring methoxyphenol apocynin has been found to inhibit NADPH oxidase upon activation by peroxidases (e.g. soybean peroxidase, myeloperoxidase) or ROS under mild reaction conditions. Upon peroxidase-catalyzed activation, the apocynin oxidation products act to block the assembly and activation of NADPH oxidase. Although the mechanism of inhibition of NADPH oxidase remains largely unknown, apocynin's high effectiveness and low toxicity makes it a promising lead compound in the development of new therapeutic agents for cardiovascular diseases.

Para-Bromophenacyl bromide alleviates airway hyperresponsiveness and modulates cytokines, IgE and eosinophil levels in ovalbumin-sensitized and -challenged mice.

Airway hyperresponsiveness, airway eosinophilia and increased IgE levels in serum are the important characteristic features of asthma. We evaluated the potential of para-Bromophenacyl bromide (PBPB), a known phospholipase A(2) inhibitor, on allergen-induced airway hyperresponsiveness in a mouse model. We sensitized and challenged mice with ovalbumin (OVA) to develop airway hyperresponsiveness as assessed by airway constriction and airway hyperreactivity (AHR) to methacholine (MCh) induced by allergen. The mice were orally treated with PBPB (0.1, 1 and 10 mg/kg) during or after OVA-sensitization and OVA-challenge to evaluate its protective or reversal effect on airway constriction and AHR to MCh. Determination of OVA-induced airway constriction and AHR to MCh were performed by measuring specific airway conductance (SGaw) using non-invasive dual-chamber whole body-plethysmography. We observed that PBPB (1 mg/kg) significantly reduced OVA-induced airway constriction and AHR to MCh (p<0.01). PBPB (1 mg/kg) treatment significantly inhibited PLA(2) activity in the BAL fluid. Cytokine analysis of the BAL fluid revealed that PBPB caused an increase in interferon-gamma (IFN-gamma) (p<0.02) and a decrease in interleukin-4 (IL-4) (p<0.05) and interleukin-5 (IL-5) (p<0.05) levels. The OVA-specific serum IgE levels (p<0.01) and the BAL eosinophils (p<0.001) were also reduced significantly. Thus, PBPB is capable of modulating allergen induced cytokine levels and serum IgE levels, and alleviating allergen induced airway hyperresponsiveness and eosinophils in mice. These data suggest that PBPB could be useful in the development of novel agents for the treatment of allergen induced airway hyperresponsiveness.

Pharmacokinetic-pharmacodynamic interaction between BIA 3-202, a novel COMT inhibitor, and levodopa/benserazide.

BIA 3-202 is a novel catechol-O-methyltransferase (COMT) inhibitor being developed for use as a levodopa-sparing agent in Parkinson's disease. This study investigated the effect of four single oral doses of BIA 3-202 (50 mg, 100 mg, 200 mg, and 400 mg) compared with placebo on plasma concentrations of levodopa and its metabolite 3- O-methyl-levodopa (3-OMD) and on inhibition of erythrocyte COMT in healthy subjects receiving 100 mg of levodopa and 25 mg of benserazide (Madopar 125). This was a single-centre, double-blind, placebo-controlled, randomised, crossover study with five single-dose treatment periods. The washout period between doses was 2 weeks. On each treatment period, a different dose of BIA 3-202 or placebo was administered concomitantly with Madopar 125. Tolerability was assessed by recording adverse events, vital signs, continuous electrocardiogram and clinical laboratory parameters. In the study, 18 subjects (12 male and 6 female) participated. The drug combination was well tolerated. All doses of BIA 3-202 significantly increased the area under the concentration-time curve (AUC) versus placebo, ranging from 39% (95% confidence intervals, 1.06-1.69) with 50 mg to 80% (95% confidence intervals, 1.42-2.22) with 400 mg. No significant change in mean maximum plasma concentrations (C(max)) of levodopa was found. Mean C(max) and AUC of 3-OMD significantly decreased for all doses tested. BIA 3-202 caused a rapid and reversible inhibition of S-COMT activity, ranging from 57% (50 mg) to 84% (400 mg). In conclusion, the novel COMT inhibitor BIA 3-202 was well tolerated and significantly increased the bioavailability of levodopa and reduced the formation of 3-OMD when administered with standard release levodopa/benserazide.

Higher plasma 5-hydroxyindoleacetic acid levels are associated with SSRI-induced nausea.

We investigated the association between selective serotonin reuptake inhibitors (SSRIs; paroxetine or fluvoxamine) and nausea with regard to plasma 5-hydroxyindoleacetic acid (p5-HIAA) levels. Forty-eight patients meeting the DSM-IV criteria for major depressive disorder and treated with paroxetine or fluvoxamine participated in this study. p5-HIAA levels after SSRI administration were significantly higher in the nausea group than those in the nonnausea group (nausea group: 8.0 +/- 4.6 ng/ml; nonnausea group: 3.6 +/- 2.2 ng/ml; p < 0.01). On the other hand, no significant difference was found between the nausea and nonnausea group in terms of p5-HIAA levels before each drug administration. These results suggest that SSRI-induced nausea is associated with serotonergic hyperactivity in the gastrointestinal tract.

Allergic contact dermatitis from a paper mill slimicide containing 2-bromo-4'-hydroxyacetophenone.

Slimicides are biocidal products used in paper mills to inhibit the proliferation of slime-forming microorganisms that would otherwise spoil the paper products. A laboratory technician working at a paper mill had recurring dermatitis related to contact with the slimicide Busan 1130. We report the first case of allergic contact dermatitis from the slimicide Busan 1130. Diagnostic patch testing was performed with solutions of Busan 1130 and its active ingredient, 2-bromo-4'-hydroxyacetophenone (BHAP). Twenty-five controls were also tested. The patient showed a ++ reaction to 0.1% Busan 1130 aqueous solution and 0.01% BHAP in ethanol. All controls were negative. The patient had recurrent allergic contact dermatitis from exposure to BHAP contained in the slimicide Busan 1130.

AVANTI 1: randomized, double-blind trial to evaluate the efficacy and safety of zidovudine plus lamivudine versus zidovudine plus lamivudine plus loviride in HIV-infected antiretroviral-naive patients. AVANTI Study Group.

The objective of this randomized double-blind, placebo-controlled trial was to investigate the effect of combination antiretroviral therapy on plasma HIV-1 RNA as measured by HIV RNA PCR and to assess the safety and tolerability of such regimens. The trial was carried out in seven European countries, Australia and Canada and involved antiretroviral-naive patients (n = 106) with CD4 counts between 150-300 cells/mm3 (CDC group A) and 150-500 cells/mm3 (CDC group B/C). Patients were randomly assigned to zidovudine (200 mg three times daily) plus lamivudine (300 mg twice daily) or to zidovudine plus lamivudine plus loviride (100 mg three times daily) for 52 weeks. The main outcome measures were degree and duration of reduction of plasma HIV-1 RNA as measured by RNA PCR and the development of drug-related toxicities sufficiently severe to warrant dose modification, interruption or permanent discontinuation. A mild, though statistically significant difference in favour of zidovudine plus lamivudine plus loviride for log10 plasma HIV-1 RNA (P = 0.022), as compared to zidovudine plus lamivudine, was observed using area-under-the-curve minus baseline (AUCMB). An increase in CD4 cell count in the zidovudine plus lamivudine plus loviride group was observed with a median improvement of 124 cells/mm3 at week 52 compared with 70 cells/mm3 in the zidovudine plus lamivudine group (P = 0.06). Both treatment regimens were well tolerated.