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Introduction: Tert-butylphenol (TBP) derivatives, antioxidants in adhesives and diabetes devices, may provoke allergic contact dermatitis (ACD)., Objectives: The objective of this study is to report sensitization to TBP derivatives in medical devices and to highlight that tert-butylhydroquinone (BHQ) and tert-butylcatechol (TBC) are potential screeners in this regard., Methods: Fifteen patients with ACD from adhesives and diabetes devices were patch tested to different TBPs: BHQ 1% pet., TBC 0.25% pet., BHA 2% pet., BHT 2% pet., 4-tert-butylphenol (TBP) 1% pet. and 2,4-di-tert-butylphenol (di TBP) 1% pet. The culprit devices (medical adhesives, sanitary pads, diabetes devices) and TBP patch preparations were analysed using gas chromatography-mass spectrometry (GC-MS)., Results: BHQ (9/13), TBC (7/13), and to a lesser extent BHT (3/15), BHA (2/15) and TBP (2/13) gave positive reactions. Seven patients had developed ACD from adhesives and diabetes devices, respectively, and one patient from sanitary pads. GC-MS analyses of the medical devices and patch test materials confirmed the presence of the patch-test positive TBPs, or chemically related derivatives, or, interestingly, tert-butylbenzoquinones (BBQ) were found, that is, spontaneously formed, highly reactive TBP metabolites, likely (pseudo-) cross reacting with the patch tested TBPs., Conclusion: TBPs might be overlooked sensitizers in medical devices, and BHQ and TBC are potential screeners in this regard., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: For Parkinson disease (PD) patients who have been diagnosed with advanced disease that can no longer be effectively controlled with optimized oral or transdermal medications, a range of device-aided therapies (DAT) are available, comprising either deep brain stimulation or infusion therapies providing continuous dopaminergic stimulation. Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion is the latest DAT for advanced PD (APD) that was approved in Romania in 2021., Study Question: What is the experience to date in real-world clinical practice in Romania regarding the efficacy and tolerability of LECIG in APD?, Study Design: A retrospective evaluation of 74 APD patients treated with LECIG at 12 specialized APD centers in Romania., Measures and Outcomes: Demographic data and various clinical parameters were recorded, including Mini Mental State Evaluation score or Montreal Cognitive Assessment Test score. Levodopa-equivalent daily dose and the administered doses of levodopa and other PD medications were evaluated at baseline and after starting LECIG treatment. The efficacy of LECIG in reducing daily hours of off time, motor fluctuations, and dyskinesias were assessed. Any percutaneous endoscopic gastrojejunostomy system or device complications after starting LECIG treatment were noted., Results: At baseline, patients were taking oral levodopa for a mean of 5.3 times per day, with a high proportion also taking concomitant add-on therapies (dopamine agonists, 86%, monoamine oxidase type-B inhibitors, 53%; catechol-O-methyltransferase inhibitors, 64%). LECIG treatment significantly reduced daily off time versus baseline from 5.7 h/d to 1.7 hours per day ( P < 0.01). Duration and severity of dyskinesias was also significantly reduced versus baseline, and improvements were observed in Hoehn and Yahr Scale scores. LECIG treatment also allowed a significant reduction in the use of concomitant oral medications., Conclusions: These findings suggest that LECIG treatment is an effective DAT option in APD that can simplify the treatment regimen., Competing Interests: J. A. Szász consultant and speaking honoraria: AbbVie, Boehringer-Ingelheim, GSK, Lundbeck, Novartis, Pfizer, Stada, Teva, and UCB. V. A. Constantin speaking honoraria: AbbVie, Bayer, UCB, Pfizer, Stada, Ewopharma, Lundbeck and Wörwag Pharma. A. O. Dulamea has served as a scientific advisor or speaker for Novartis, Merck, Roche, Sanofi Genzyme, Genesis Pharma, Krka, Gedeon Richter, Eli Lilly, Wörwag Pharma, Zentiva, Takeda, Janssen, AbbVie, and Stada. C. Tiu speaker's honoraria from Merck, Genzyme, Roche, Janssen, Novartis, Boehringer Ingelheim, and Pfizer. L. P. Dumbravă consultant and speaking honoraria: Sanofi, Roche, SC Bayer, UCB Pharma, Ipsen Pharma, Bristol Myers Squib, Pfizer, AbbVie, Stada M&D, and Vedra International. A. Ene speaker honoraria: AbbVie, Stada, Pfizer, Genesis, and Worwag. M. Lungu speaker honoraria from AbbVie, Boehringer-Ingelheim, Stada M&D, and Bayer. A. Axelerad speaker honoraria from AbbVie, Boehringer-Ingelheim, GSK, Lundbeck, Novartis, Pfizer, Stada, Teva, UCB, Wörwag Pharma, Sanofi, Krka, Gedeon Richter, Eli Lilly, Zentiva, Takeda, Janssen, Zentiva, Merck, Roche, and Ipsen Pharma. M. Simu honoraria for advisory boards and educational lectures from: AbbVie, Astra Zeneca, Biogen, Boehringer Ingelheim, Pfizer, UCB, Servier, Teva, Merck, Ever Pharma, Roche, and Novartis A. G. Danci speaker honoraria from Teva, Stada and Ipsen Pharma. Sabău Monica consultant and speaking honoraria: Bayer, AstraZeneca, Roche, AbbVie, Pfizer, Novartis, Sanofi, Johnson& Johnson, Merk, Stada, SunWave Pharma, Ewopharma, Krka, and Elly Lilly. C. Falup-Pecurariu received royalties from Elsevier and Springer Verlag honoraria from AbbVie and the International Parkinson's Disease and Movement Disorders Society, outside of the present work. Ş. Strilciuc discloses an academic grant from Pfizer Inc (Delaware, US), unrelated to this manuscript. The remaining authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Levodopa treatment requires the addition of other drugs, such as catechol-O-methyl transferase (COMT) inhibitors, to alleviate motor fluctuations in advanced parkinson's disease (PD). However, the optimal strategy, including the type and dose of COMT inhibitors remains unknown. This systematic review and network meta-analysis aimed to assess the efficacy and safety of different COMT inhibitors and for treating PD patients., Methods: PubMed, Embase, Cochrane Library and Web of Science were screened up to November 20, 2022. Randomized controlled trials (RCTs) of COMT inhibitors (entacapone, opicapone, tolcapone) for PD patients were included. Eligible outcomes were total ON-time, rate of ON-time >1 h, total daily dose of levodopa therapy, mean change from baseline to final follow up in Unified Parkinson's Disease Rating Scale (UPDRS) part III scores, adverse events and dyskinesia. Network meta-analyses integrated direct and indirect evidence with placebo as a common comparator., Results: We identified 18 studies with 7564 patients. Opicapone, entacapone, and tolcapone could increase total ON-time when compared with placebo. However, opicapone (25 mg, MD 4.0, 95%CrI: 1.1-7.5) and opicapone (50 mg, MD 5.1, 95%CrI: 2.2-8.7) statistically significant increase the total ON-time. opicapone and entacapone could increase the rate of ON-time >1 h when compared with placebo. Only opicapone (5 mg) showed no statistically significant with placebo (OR 1.4, 95%CrI: 0.74-2.4). We found that opicapone (50 mg, SURCA, 0.796) is the best option compared with other treatments. TOL (200 mg) was ranked highest in the rank probability test for total daily dose of levodopa therapy, followed by OPI (50 mg), TOL (400 mg) and TOL (100 mg) in order. SUCRA rankings identified TOL (200 mg) as the most likely therapy for increasing adverse events (SUCRA 27.19%), followed by TOL (400 mg, SUCRA 27.20%) and OPI (5 mg, SUCRA 30.81%). The SUCRA probabilities were 91.6%, 75.2%, 67.9%, 59.3%, 45.6%, 41.1%, 35.1%, 24.6% and 9.4% for PLA, TOL (400 mg), ENT (100 mg), ENT (200 mg), OPI (5 mg), TOL (100 mg), OPI (25 mg), OPI (50 mg), and TOL (200 mg) respectively., Conclusion: In conclusion, opicapone (50 mg) may be a better choice for treatment PD when compared with other COMT inhibitors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Pseudomonas aeruginosa is a ubiquitous human pathogen that causes severe infections. Although antibiotics, such as tobramycin, are currently used for infection therapy, their antibacterial activity has resulted in the emergence of multiple antibiotic-resistant bacteria. The 6-gingerol analog, a structural derivative of the main component of ginger, is a quorum sensing (QS) inhibitor. However, it has a lower biofilm inhibitory activity than antibiotics and the possibility to cause toxicity in humans. Therefore, novel and more effective approaches for decreasing dosing concentration and increasing biofilm inhibitory activity are required to alleviate P. aeruginosa infections. In this study, a 6-gingerol analog was combined with tobramycin to treat P. aeruginosa infections. The combined treatment of 6-gingerol analog and tobramycin showed strong inhibitory activities on biofilm formation and the production of QS-related virulence factors of P. aeruginosa compared to single treatments. Furthermore, the combined treatment alleviated the infectivity of P. aeruginosa in an insect model using Tenebrio molitor larvae without inducing any cytotoxic effects in human lung epithelial cells. The 6-gingerol analog showed these inhibitory activities at much lower concentrations when used in combination with tobramycin. Adjuvant effects were observed through increased QS-disrupting processes rather than through antibacterial action. In particular, improved RhlR inactivation by this combination is a possible target for therapeutic development in LasR-independent chronic infections. Therefore, the combined treatment of 6-gingerol analog and tobramycin may be considered an effective method for treating P. aeruginosa infections. IMPORTANCE Pseudomonas aeruginosa is a pathogen that causes various infectious diseases through quorum-sensing regulation. Although antibiotics are mainly used to treat P. aeruginosa infections, they cause the emergence of resistant bacteria in humans. To compensate for the disadvantages of antibiotics and increase their effectiveness, natural products were used in combination with antibiotics in this study. We discovered that combined treatment with 6-gingerol analog from naturally-derived ginger substances and tobramycin resulted in more effective reductions of biofilm formation and virulence factor production in P. aeruginosa than single treatments. Our findings support the notion that when 6-gingerol analog is combined with tobramycin, the effects of the analog can be exerted at much lower concentrations. Furthermore, its improved LasR-independent RhlR inactivation may serve as a key target for therapeutic development in chronic infections. Therefore, the combined treatment of 6-gingerol analog and tobramycin is suggested as a novel alternative for treating P. aeruginosa infections.

Introduction: Parkinson's disease (PD) is a progressive, chronic neurodegenerative disorder. The main neuropathological cause of the disease is the death of dopaminergic neurons in the substantia nigra. Unfortunately, there is no curative treatment yet. The gold-standard of the treatment is levodopa (LD). During the course of the disease, motor complications develop, which postulates the addition of entacapone (ENT) to the dopaminergic medication. Previous studies have suggested that patients have a better quality of life when entacapone is added in a combination with LD., Areas Covered: A systematic literature search was performed. Articles were identified through PubMed (MEDLINE), Web of Science, Ovid, and ClinicalTrials.gov databases. The following search terms were used: 'Levodopa' AND 'Carbidopa' OR 'Benserazide' AND 'Entacapone'. The search period was between 2000 and 2020. Twenty randomized and 10 non-randomized clinical trials (12,893 subjects) were included in the qualitative analysis. The systematic review was written in line with the PRISMA guideline., Expert Opinion: ENT administered in combination with LD resulted in a better quality of life compared to separate tablets. Therefore, in PD patients where impaired motor performance develops and the application of entacapone is necessary, it is suggested to be administered in a single tablet form.

Motor fluctuations are frequently seen in Parkinson disease patients on chronic treatment with levodopa. Management of motor fluctuation includes the addition of catechol-O-methyl transferase (COMT) inhibitors. Opicapone is a recent and selective third-generation COMT inhibitor which achieves marked increase in the bioavailability of levodopa. We present a consensus of a group of Spanish neurologists with extensive experience in the clinical management of motor fluctuations. The clinical experience of this group of experts is in line with clinical trials and confirms that opicapone is an effective drug in the control of motor fluctuations, regardless of the daily levodopa dose, or the use of other antiparkinsonian drugs. However, in the opinion of these experts, the ideal patient with Parkinson's disease to initiate treatment with opicapone is the one with mild motor fluctuations, since the ratio between clinical efficacy and adverse effects is more favorable. In general, it is an easy-to-use drug both in those first treated with a COMT inhibitor or those already on entacapone. In any case, the secondary side effects are easily managed.

Background: Urushiol, the culprit allergen in Toxicodendron plants such as poison ivy, is an oily mixture of 15 and 17 carbon side chain alk-(en)-yl catechols. Recently, consumer products have been identified that contain Toxicodendron as an ingredient on their label; however, no studies have assessed whether urushiol is indeed present within these products., Objective: The aim of the study was to determine whether urushiol compounds are present in consumer products labeled as containing Toxicodendron species., Methods: Gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry were performed on 9 consumer products labeled as containing Toxicodendron species, including topical homeopathic remedies. Single ion monitoring gas chromatography-mass spectrometry was programmed in selective ion mode to detect 3-methylcatechol characteristic fragment ions of alk-(en)-yl catechols after silanization. Similarly, single ion monitoring liquid chromatography-tandem mass spectrometry was programmed to detect 4 urushiol pentadecylcatechols and 5 urushiol heptadecylcatechols using previously reported mass-to-charge ratios., Results: Gas chromatography-mass spectrometry detected alk-(en)-yl catechols in 67% (6/9) of the products tested. Liquid chromatography-tandem mass spectrometry detected multiple urushiol pentadecylcatechols and heptadecylcatechols in 44% (4/9) of the products tested., Conclusions: Alk-(en)-yl catechols and multiple urushiols were detected in consumer products listing Toxicodendron species as an ingredient. Clinicians should be aware of these known allergenic ingredients in consumer products.

Candida albicans is an opportunistic pathogen and responsible for candidiasis. C. albicans readily forms biofilms on various biotic and abiotic surfaces, and these biofilms can cause local and systemic infections. C. albicans biofilms are more resistant than its free yeast to antifungal agents and less affected by host immune responses. Transition of yeast cells to hyphal cells is required for biofilm formation and is believed to be a crucial virulence factor. In this study, six components of ginger were investigated for antibiofilm and antivirulence activities against a fluconazole-resistant C. albicans strain. It was found 6-gingerol, 8-gingerol, and 6-shogaol effectively inhibited biofilm formation. In particular, 6-shogaol at 10 μg/ml significantly reduced C. albicans biofilm formation but had no effect on planktonic cell growth. Also, 6-gingerol and 6-shogaol inhibited hyphal growth in embedded colonies and free-living planktonic cells, and prevented cell aggregation. Furthermore, 6-gingerol and 6-shogaol reduced C. albicans virulence in a nematode infection model without causing toxicity at the tested concentrations. Transcriptomic analysis using RNA-seq and qRT-PCR showed 6-gingerol and 6-shogaol induced several transporters ( CDR1, CDR2 , and RTA3 ), but repressed the expressions of several hypha/biofilm related genes ( ECE1 and HWP1 ), which supported observed phenotypic changes. These results highlight the antibiofilm and antivirulence activities of the ginger components, 6-gingerol and 6-shogaol, against a drug resistant C. albicans strain.

Background: An increased incidence of prostate cancer was observed in Parkinson's disease (PD) patients treated with entacapone during a pre-approval randomized clinical trial; the relation has not been robustly investigated in the U.S. ambulatory setting., Objective: To investigate whether entacapone is associated with prostate cancer and to assess whether the associations are correlated with advanced disease at the time of cancer diagnosis., Methods: Using data from the Department of Veterans Affairs healthcare system, new-user cohorts were created of PD patients treated with add-on entacapone or add-on dopamine agonist/monoamine oxidase B inhibitors between January 2000 and December 2014. Patients were followed on-treatment for occurrence of prostate cancer, identified via linkage to the VA cancer registry., Results: Mean follow-up time was 3.1 and 4.0 years in the entacapone and control cohort, respectively. There were 17,666 subjects meeting study criteria (mean age, 74 (SD 8.6) years); the entacapone-treated group comprised 5,257 subjects. Twenty-three prostate cancer cases occurred in the entacapone cohort and ninety-seven in the control cohort. The overall incidence of prostate cancer was 1.8 per 1,000 person-years of risk. There was no difference in risk of prostate cancer between the cohorts for increased duration of entacapone intake (adjusted HR: 1.08; 95% confidence interval: 0.46-2.51 for cumulative exposure of ≥2 years). Time since starting drug therapy and cumulative dose (mg) also do not suggest a difference in prostate cancer risk between cohorts., Conclusions: Prolonged therapy with entacapone was not associated with increased prostate cancer incidence; however, findings suggest a higher severity of prostate cancer., (Published by Elsevier Ltd.)

Background: Poison ivy, poison oak, and poison sumac are the most common causes of allergic contact dermatitis in North America. Although extensive efforts have been made to develop therapies that prevent and treat allergic contact dermatitis to these plants, there lacks an entirely effective method, besides complete avoidance. Efforts to develop a more effective preventive therapy, such as a vaccine, are ongoing. To accurately evaluate the efficacy of these new therapies, an appropriate assessment tool is needed., Objective: The aim of this study was to evaluate the safety and appropriate doses of urushiol required for a patch test based on the hydrogel delivery system of the Thin-Layer Rapid Use Epicutaneous Patch Test., Methods: Nine subjects were patch tested with various doses of urushiol and a negative control on day 0. Patch test sites were inspected for any local reaction on days 2, 4, 7, 14, and 21 after the initial exposure and graded by standard morphology., Conclusions: All 9 subjects did not have any significant adverse effects. The urushiol patch test using the hydrogel delivery method demonstrated urushiol sensitivity. All doses of urushiol resulted in a local reaction, and severity of reactions was correlated with dosage of urushiol used in the patch test.

Background: A qualified consensus suggests that a combination of levodopa with a peripherally acting dopa decarboxylase inhibitor continues to present the gold standard treatment of Parkinson's disease (PD). However, as the disease progresses the therapeutic window of levodopa becomes narrowed. Pharmacological strategies for motor fluctuations are focused on providing less pulsatile and more continuous dopaminergic stimulation. Peripheral catechol-O-methyltransferase (COMT) inhibition improves the bioavailability of levodopa and results in a prolonged response., Objective: The primary aim of this study was to investigate the efficacy and safety of the two available COMT inhibitors; entacapone and tolcapone and the recently introduced opicapone., Methods: Electronic databases were systematically searched for original studies published within the last 37 years. In addition, lists of identified studies, reviews and their references were examined., Results: Twelve studies fulfilled the inclusion criteria. 3701 patients with PD were included in this systematic review., Conclusions: Adjuvant treatment of PD patients experiencing motor fluctuations with entacapone resulted in improvement of motor function and was well tolerated. Therefore, entacapone presented an acceptable benefit to risk ratio. Tolcapone appeared to result in a greater therapeutic effect. However, this was not consistent across all motor variables and studies, and thus would not support its use, given the current onerous monitoring that is required. Opicapone was not associated with adverse reactions in a phase III trial but did not present a greater efficacy than entacapone, and thus further studies are required in order to illustrate its cost effectiveness.

The objective of the present study was to characterize the role of novel resveratrol (Res) analogs: 4-(E)-{(4-hydroxyphenylimino)-methylbenzene, 1, 2-diol} (HPIMBD) and 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) as potent antioxidants against breast cancer. Non-neoplastic breast epithelial cell lines MCF-10A and MCF-10F were treated with 17β-estradiol (E2), Res, HPIMBD, and TIMBD for up to 72 h. mRNA and protein levels of antioxidant genes, superoxide dismutase 3 (SOD3) and N-quinoneoxidoreductase-1 (NQO1) and transcription factors, nuclear factor erythroid 2-related factor (Nrf) 1, 2 and 3 were quantified after the above treatments. Generation of reactive oxygen species (ROS) was measured by CM-H2-DCFDA and oxidative-DNA damage was determined by measuring 8-hydroxy-2-deoxyguanosine (8-OHdG). HPIMBD and TIMBD scavenged cellular ROS production, attenuated oxidative DNA damage, increased mRNA and protein expression levels of SOD3 and NQO1 and activated Nrf signaling pathway. Our studies demonstrate that HPIMBD and TIMBD have the potential as novel antioxidants to prevent development of breast cancer., (© 2017 Wiley Periodicals, Inc.)

Chemical-induced depigmentation of the skin has been recognized for more than 75 years, first as an occupational hazard but then extending to those using household commercial products as common as hair dyes. Since their discovery, these chemicals have been used therapeutically in patients with severe vitiligo to depigment their remaining skin and improve their appearance. Because chemical-induced depigmentation is clinically and histologically indistinguishable from nonchemically induced vitiligo, and because these chemicals appear to induce melanocyte autoimmunity, this phenomenon should be known as "chemical-induced vitiligo," rather than less accurate terms that have been previously used., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: To assess the efficacy and safety of adjuvant treatment with entacapone in the treatment of later Parkinson's disease (PD) patients with motor fluctuation., Methods: We conducted a systematic review of relevant studies from 8 databases to June 23, 2016., Results: Fourteen studies were included in this review (n = 2,804). The results showed that compared with placebo, adjuvant therapy with entacapone significantly increased on time (p < 0.01) and reduced off time (p < 0.01), the required levodopa (LD) dose (p < 0.01) and improved Parkinson's Disease Rating Scale (UPDRS) scores (activities of daily living score: p < 0.01; motor score: p < 0.01; UPDRS I-III score: p > 0.05). However, the withdrawal (OR 1.44, 95% CI 1.10-1.89, p < 0.01) due to adverse events and adverse events rates including nausea (OR 2.23, 95% CI 1.56-3.20, p < 0.01), urine discoloration (OR 14.99, 95% CI 7.63-29.44, p < 0.01), gastrointestinal disorder (OR 2.6, 95% CI 1.89-3.57, p < 0.01) and dyskinesia (OR 2.00, 95% CI 1.56-2.58, p < 0.01) increased in patients with entacapone compared with those given a placebo ., Conclusions: This meta-analysis suggests that the entacapone used as adjuvant therapy to LD is effective in the management of later PD with fluctuation. However, patients on entacapone had a higher frequency of adverse events than those on placebo but no occurrence of severe adverse reactions., (© 2017 S. Karger AG, Basel.)

Poison ivy-induced allergic contact dermatitis (ACD) is the most common environmental allergic condition in the United States. Case numbers of poison ivy ACD are increasing due to growing biomass and geographical expansion of poison ivy and increasing content of the allergen, urushiol, likely attributable to rising atmospheric CO 2 Severe and treatment-resistant itch is the major complaint of affected patients. However, because of limited clinical data and poorly characterized models, the pruritic mechanisms in poison ivy ACD remain unknown. Here, we aim to identify the mechanisms of itch in a mouse model of poison ivy ACD by transcriptomics, neuronal imaging, and behavioral analysis. Using transcriptome microarray analysis, we identified IL-33 as a key cytokine up-regulated in the inflamed skin of urushiol-challenged mice. We further found that the IL-33 receptor, ST2, is expressed in small to medium-sized dorsal root ganglion (DRG) neurons, including neurons that innervate the skin. IL-33 induces Ca 2+ influx into a subset of DRG neurons through neuronal ST2. Neutralizing antibodies against IL-33 or ST2 reduced scratching behavior and skin inflammation in urushiol-challenged mice. Injection of IL-33 into urushiol-challenged skin rapidly exacerbated itch-related scratching via ST2, in a histamine-independent manner. Targeted silencing of neuronal ST2 expression by intrathecal ST2 siRNA delivery significantly attenuated pruritic responses caused by urushiol-induced ACD. These results indicate that IL-33/ST2 signaling is functionally present in primary sensory neurons and contributes to pruritus in poison ivy ACD. Blocking IL-33/ST2 signaling may represent a therapeutic approach to ameliorate itch and skin inflammation related to poison ivy ACD., Competing Interests: The authors declare no conflict of interest.

Entacapone is frequently used together with levodopa/carbidopa (LC) and levodopa/benserazide (LB) in the treatment of Parkinson's disease (PD) patients with wearing-off symptoms. It is generally assumed that the effects of entacapone are independent of the type of decarboxylase inhibitor used, but there is very little published data available on the efficacy of entacapone administered with LB versus LC. We have performed a pooled analysis of three randomized, double-blind, 6-month, phase III studies to compare the treatment effects of entacapone (compared to placebo) in PD patients receiving LC or LB. A total of 551 PD patients experiencing wearing-off were included in the analysis. 300 patients were on LB and 251 on LC at baseline. At 6 months, entacapone (compared to placebo) improved mean daily OFF-time in patients on LB and LC by 0.76 (p = 0.016) and 0.95 (p = 0.011) hours, respectively. The corresponding improvements in ON-time were 0.97 (p = 0.002) and 0.83 h (p = 0.022), respectively. The treatment effects of entacapone both in LB and LC users were statistically significant (p < 0.05) also in UPDRS II and III scores, except in UPDRS II scores in patients receiving LC (p = 0.20). None of the treatment effects of entacapone were statistically significantly different between patients receiving LB or LC. Reported adverse events were comparable between LB and LC users. We conclude that entacapone provided comparable benefits in PD patients with wearing-off symptoms using either LB or LC.

IPX066 (extended-release carbidopa-levodopa [ER CD-LD]) is an oral extended-release capsule formulation of carbidopa and levodopa. The single-dose pharmacokinetics of ER CD-LD (as 2 capsules; total dose, 97.5 mg-390 mg CD-LD) versus immediate-release (IR) CD-LD (25 mg-100 mg), sustained-release (CR) CD-LD (25 mg-100 mg), and CD-LD-entacapone (25 mg-100 mg-200 mg) was evaluated in healthy subjects. Following IR dosing, LD reached peak concentrations (Cmax ) at 1 hour; LD concentrations then decreased rapidly and were less than 10% of peak by 5 hours. With CR CD-LD and CD-LD-entacapone, LD Cmax occurred at 1.5 hours, and concentrations were less than 10% of peak by 6.3 and 7.5 hours, respectively. The initial increase in LD concentration was similar between ER CD-LD and IR CD-LD and faster than for CR CD-LD and CD-LD-entacapone. LD concentrations from ER CD---LD were sustained for approximately 5 hours and did not decrease to 10% of peak until 10.1 hours. Dose-normalized LD Cmax values for ER CD-LD were significantly lower (P< .05) than for the other CD-LD products. Bioavailability of LD from ER CD-LD was 83.5%, 78.3%, and 58.8% relative to IR CD-LD, CR CD-LD, and CD-LD-entacapone, respectively., (© 2015 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Background: The association between Parkinson's disease (PD) and prostate cancer, both common in elderly men, is disputable. In the STRIDE-PD study, prostate cancer developed in 9 patients (3.7%) receiving levodopa/carbidopa with entacapone, a catechol-O-methyltransferase inhibitor, versus 2 cases (0.9%) without entacapone. The current pharmacoepidemiological study aimed to determine whether entacapone increases prostate cancer incidence or mortality in PD patients and whether cumulative exposure affects these rates., Methods: We performed a retrospective cohort study using population-wide health care registers with patient-level linkage. Prostate cancer incidence and mortality were modeled by Cox's proportional hazards models., Results and Conclusions: Use of entacapone with l-dopa/dopa decarboxylase inhibitor caused no increased risk of prostate cancer incidence (hazard ratio [HR]: 1.05; 95% confidence interval: 0.76-1.44) or mortality (0.93; 0.43-1.98). The HR for cumulative entacapone use of >360 days versus never-use was 0.82 (0.56-1.18) for prostate cancer incidence and 1.27 (0.60-2.72) for prostate cancer mortality., (© 2015 International Parkinson and Movement Disorder Society.)

Background: Due to the short half-life of levodopa, immediate-release carbidopa-levodopa (IR CD-LD) produces fluctuating LD concentrations, contributing to a risk of eventual motor complications. IPX066 was designed to rapidly attain therapeutic LD concentrations and maintain them to allow a dosing interval of ∼6 hours., Objective: To extensively analyze the dosing data collected in IPX066 studies during open-label conversions from IR CD-LD alone or with entacapone (CLE) and identify patterns relevant for managing conversion in the clinical setting., Methods: Patients had ≥2.5 hours/day of "off" time despite a stable IR or CLE regimen. Suggested initial dosing conversion tables based on prior LD daily dosage were provided., Results: Of 450 patients previously treated with IR CD-LD and 110 with CLE, 87.3% and 82.7% completed conversion to IPX066, respectively. At the end of conversion, average IPX066 LD daily dosages were higher than pre-conversion dosages, with a mean conversion ratio of 2.1±0.6 for IR CD-LD and 2.8±0.8 for CLE; >90% of patients took IPX066 3 or 4 times/day, compared with a median of 5 times/day at baseline in both studies. After conversion, daily "off" time significantly decreased, with no significant increase in troublesome dyskinesia. The most common adverse event reported during conversion was nausea, with an incidence of 5.3% for conversion from IR and 7.3% from CLE., Conclusions: Among PD patients with substantial "off" time, a majority were safely converted to IPX066. The sustained LD profile from the IPX066 formulation allowed an increase in LD dose accompanied by improved motor functions, without increased troublesome dyskinesia.

Background and Objectives: Opicapone is a novel third generation catechol-O-methyltransferase (COMT) inhibitor. The purpose of this study was to compare the levodopa pharmacokinetic profile throughout a day driven by the COMT inhibition either following repeated doses of opicapone or concomitant administration with entacapone., Methods: A randomized, double-blind, gender-balanced, parallel-group study was performed in 4 groups of 20 healthy subjects each. Four subjects in each group received placebo during the entire study. Sixteen subjects in one group received placebo once daily for 11 days and on day 12, 200 mg entacapone concomitantly with each levodopa/carbidopa dose (three times separated by a 5-h interval). Sixteen subjects in each of the remaining three groups received respectively 25, 50, and 75 mg opicapone once daily for 11 days and on day 12, placebo concomitantly with each levodopa/carbidopa dose., Results: Levodopa minimum plasma concentration (Cmin) for each levodopa/carbidopa dose and for the mean of all levodopa/carbidopa doses increased substantially with all active treatments (entacapone and opicapone) when compared to the control group (placebo), with values ranging from 1.7-fold (200 mg entacapone) to 3.3-fold (75 mg opicapone). No statistical difference was found for levodopa peak of systemic exposure (as assessed by maximum observed plasma concentration (Cmax)) between all active treatments and placebo. A significant increase in the levodopa extent of systemic exposure (as assessed by concentration-time curve (AUC)) occurred with all opicapone treatments in relation to placebo. No statistical difference was found for levodopa AUC when entacapone was compared to placebo. When compared to entacapone, both 50 and 75 mg opicapone presented a significant increase for the levodopa AUC. All active treatments significantly inhibited both peak (as assessed by Emax) and extent (as assessed by effect-time curve (AUEC)) of the COMT activity in relation to placebo. When compared to entacapone, all opicapone treatments significantly decreased the extent (AUEC) of the COMT activity due to a long-lasting and sustained effect. The tolerability profile was favorable for all active treatments., Conclusion: Opicapone, a novel third generation COMT inhibitor, when compared to entacapone, provides a superior response upon the bioavailability of levodopa associated to more pronounced, long-lasting, and sustained COMT inhibition. The tolerability profile was favorable. On the basis of the results presented in this study and along with the earlier pharmacology studies, it is anticipated that opicapone adjunct therapy at the dosages of 25 and 50 mg will provide an enhancement in levodopa availability that will translate into clinical benefit for Parkinson's disease patients.

The unique needs of patients with Parkinson disease challenge staff when such patients are admitted to hospitals or nursing facilities. Prolongation of the hospital stay, falls with injuries, fainting, or declining motor function may result from therapeutic misadventures or failure to anticipate common problems. Staff familiarity with Parkinson disease, and especially carbidopa-levodopa dosing and dynamics, may prevent such problems and streamline hospital and nursing home care., (Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the efficacy and tolerability of the three component drug stalevo in the treatment of patients with Parkinson's disease (PD)., Material and Methods: We analyzed the experience of using the antiparkinsonian drug stalevo (levodopa/carbidopa/entacapone) in the treatment of acute stages of PD and elderly patients with restricted possibilities of using other antiparkinsonian drugs. The study included 47 patients. A clinical example is presented. RESULTS AND СONCLUSION: Stalevo increased motor and daily activities, reduced the severity of basic symptoms of PD and improved quality of life of the patients.

The controlled trial Stalevo Reduction in Dyskinesia Evaluation in Parkinson's Disease (STRIDE-PD) reported an unexpected increase in acute myocardial infarction (AMI) with entacapone use in patients with Parkinson's disease (PD). The authors investigated whether entacapone increased cardiovascular and mortality risk compared with the use of a non-levodopa dopamine agonist (DA) or a selective monoamine oxidase type-B inhibitor (MAOBI). Using national Medicare data, a new-user cohort of elderly patients with PD treated with entacapone was propensity score (PS) matched with new users of either DA or MAOBI. The PS model included variables for sociodemographics, cardiovascular disease, medications, prior PD treatment, and comorbidities. Cox proportional hazards regression was used to compare on-therapy time to event for AMI, stroke, and death with DA-MAOBI as a reference. Study cohorts included 8681 entacapone-treated and 17,362 DA-MAOBI-treated initators who were followed for 2569 and 5385 person-years, respectively. Cohorts were closely balanced for all covariates. During follow-up, there were 106 AMIs, 89 strokes, and 201 deaths. The hazard ratio (HR) and 95% confidence interval (CI) associated with entacapone use was 0.86 (95% CI, 0.57-1.30) for AMI, 0.85 (95% CI, 0.54-1.35) for stroke, and 0.79 (95% CI, 0.58-1.07) for death. The risk was unchanged for treatment of ≤ 6 months' and>6 months' duration and was unaffected by adjustment for time-varying levodopa use during follow-up. The risk of each endpoint was not differentially affected by diabetes, ischemic heart disease, or kidney failure status. However, the risk of stroke was modified by the presence (HR, 2.09; 95% CI, 0.98-4.45) or absence (HR, 0.51; 95% CI, 0.27-0.95) of advanced PD-related morbidities (P value for interaction=0.004). Entacapone was not associated with an increased risk of AMI, stroke, or death in elderly patients with PD., (Copyright © 2013 Movement Disorder Society.)

Background: Bibrocathol is a well-established antiseptic drug for the treatment of acute eyelid diseases like blepharitis. Despite its frequent use in clinical practice, no controlled clinical trial on the efficacy of bibrocathol 2% eye ointment has been performed until now. The aim of the study was to investigate efficacy, safety and tolerability of bibrocathol (Posiformin® 2 %) eye ointment in patients diagnosed with blepharitis., Methods: In this multi-center, randomized, double-masked, placebo-controlled parallel-group comparison, the change of signs and symptoms (sum score) of blepharitis in 197 patients (ITT (intention-to-treat-group); mean age 56 ± 18 years, 56 % female, active drug:vehicle = 97:100) over 2 weeks treatment with bibrocathol 2 % eye ointment was evaluated., Results: Patients receiving bibrocathol 2 % showed greater improvement in the sum score than the placebo patients (p < 0.0001, Cohen's effect size d = 0.73). Also, the results from further efficacy assessments improvement of single symptoms and ocular discomfort measured by a VAS (visual analogue scale) supported treatment with bibrocathol. Patients and investigators provided favorable tolerability ratings preferring bibrocathol over placebo. No safety issues were observed with regard to intraocular pressure, visual acuity, or occurrence of adverse events., Conclusions: Blepharitis therapy with the antiseptic bibrocathol 2 % in this trial was highly efficacious and safe.

Scope: [6]-Gingerol, a major constituent of ginger, is considered to have several health beneficial effects. The effect of 6-gingerol on bone cells and skeleton of mice was investigated., Methods and Results: The effects of 6-gingerol on mouse bone marrow macrophages and osteoblasts were studied. 6-Gingerol-stimulated osteoclast differentiation of bone marrow macrophages but had no effect on osteoblasts. Capsazepine, an inhibitor of TRPV1 (transient receptor potential vanilloid 1) channel, attenuated the pro-osteoclastogenic effect of 6-gingerol or capsaicin (an agonist of TRPV1). Similar to capsaicin, 6-gingerol stimulated Ca(2) + influx in osteoclasts. The effect of daily feeding of 6-gingerol for 5 wk on the skeleton of adult female Balb/cByJ mice was investigated. Mice treated with capsaicin and ovariectomized (OVx) mice served as controls for osteopenia. 6-Gingerol caused increase in trabecular osteoclast number, microarchitectural erosion at all trabecular sites and loss of vertebral stiffness, and these effects were comparable to capsaicin or OVx group. Osteoclast-specific serum and gene markers of 6-gingerol-treated mice were higher than the OVx group. Bone formation was unaffected by 6-gingerol., Conclusion: Daily feeding of 6-gingerol to skeletally mature female mice caused trabecular osteopenia, and the mechanism appeared to be activation of osteoclast formation via the TRPV1 channel., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In early stages, Parkinson disease typically begins with asymmetric or unilateral motor symptoms due to combinations of mild bradykinesia, rigidity, and tremor. In most cases, with progression, signs of more generalized bradykinesia appear, which include facial masking, reduced voice volume, and slowing of activities of daily living. In more advanced Parkinson disease, other disabling manifestations may follow, such as impaired balance, gait freezing, falls, speech disturbance, and cognitive impairment. Levodopa is the most effective medical treatment for Parkinson disease. However, motor complications uniquely related to levodopa treatment may emerge that may be difficult to manage. These include fluctuating levodopa responses and involuntary movements and postures known as dyskinesia and dystonia. Medication adjustments are usually effective, but in some cases surgical intervention with deep brain stimulation becomes necessary to alleviate motor complications. The case of Mr L, a man with an 11-year history of Parkinson disease, illustrates these emerging motor complications and the manner in which they may be managed both medically and surgically.

Objectives: Several cases of syndrome of inappropriate antidiuresis induced by anti-Parkinson agents have been reported. Our previous study demonstrated that pergolide and pramipexole stimulated elevation of plasma arginine vasopressin (AVP) levels in some patients with Parkinson's disease (PD), but that levodopa/carbidopa (300/30 mg/day) did not affect plasma AVP levels in treatment-naïve PD patients. On the basis of the binding profile of ropinirole to monoamine receptors, we hypothesized that ropinirole does not stimulate AVP secretion. The aim of this study was to test this hypothesis., Methods: Inclusion criteria were patients with probable PD suffering from a wearing-off phenomenon and who had been treated using levodopa/carbidopa with or without entacapone, but not with other classes of anti-Parkinson agents. Patients were excluded if they had at least one condition that could be associated with high AVP levels. Ropinirole was initiated at 0.5 mg 3 times daily, and daily dosages were increased by 1.5 mg/day on a biweekly basis up to 6 mg/day. Plasma AVP levels were determined every two weeks. Effects of escalating ropinirole dosage on plasma AVP levels were evaluated using a one-way analysis of variance for repeated measures, an a priori Dunnett multiple comparison test, and a regression analysis., Results: Of 16 patients enrolled, 11 patients (four males and seven females) completed the study. There was no statistically significant dose-response relationship between the ropinirole dosage and plasma AVP levels., Conclusion: A minimal therapeutic dosage of ropinirole did not affect plasma AVP levels in patients with PD taking levodopa.

Levodopa remains a 'gold standard' for the treatment of patients with Parkinson's disease (PD), but its chronic use is accompanied by fluctuations of symptoms and dyskinesias related to unfavorable pharmacokinetics of levodopa and progressing loss of the nigrostriatal neurons. Prescribing inhibitors of catechol-O-methyl-transferase (enzyme of dopamine metabolism), entacapone or tolcapone, is a perspective approach to the correction of the above-mentioned complications. We followed up 402 patients with PD who received long-term therapy with a combined preparation Stalevo (levodopa/carbidopa/entacapone) for 2-5 years (2.9 ± 0.9 years). The high (92.8%) compliancy and good tolerance of the drug in patients with PD was shown. Stalevo leads to the stabilization of the response to levodopa, improvement of patients' functional capacities, increase in their everyday activity, and improvement of quality of life. Stalevo may be regarded as a preparation of choice in the treatment of motor complications in elderly patients, correction of night symptoms of PD and in a number of other clinical situations arising in hospital and outpatient practice.

Background: Urushiol is a major component of the lacquer tree which has been used as a folk remedy for the relief of abdominal discomfort in Korea. The aim of this study was to evaluate the antibacterial effects of the urushiol on Helicobacter pylori., Materials and Methods: Monomer and 2-4 polymer urushiol were used. In the in vitro study, pH- and concentration-dependent antibacterial activity of the urushiol against H. pylori were investigated. In addition, the serial morphological effects of urushiol on H. pylori were examined by electron microscopy. In vivo animal study was performed for the safety, eradication rate, and the effect on gastritis of urushiol. The expression of pro-inflammatory cytokines was checked., Results:   All strains survived within a pH 6.0-9.0. The minimal inhibitory concentrations of the extract against strains ranged 0.064-0.256 mg/mL. Urushiol caused separation of the membrane and lysis of H. pylori within 10 minutes. Urushiol (0.128 mg/mL × 7 days) did not cause complications on mice. The eradication rates were 33% in the urushiol monotherapy, 75% in the triple therapy (omeprazole + clarithromycin + metronidazole), and 100% in the urushiol + triple therapy, respectively. H. pylori-induced gastritis was not changed by urushiol but reduced by eradication. Only the expression of interleukin-1β in the gastric tissue was significantly increased by H. pylori infection and reduced by the urushiol and H. pylori eradication (p = .014)., Conclusions: The urushiol has an antibacterial effect against H. pylori infection and can be used safely for H. pylori eradication in a mouse model., (© 2011 Blackwell Publishing Ltd.)

Objective: Assess motor function and quality of life (QoL) in Parkinson's disease (PD) subjects with end-of-dose wearing off (EODWO), comparing immediate and delayed switch (IS, DEL) to levodopa/carbidopa/entacapone (LCE)., Background: LCE treatment improves motor function in PD patients with EODWO. Correlations with QoL have not been previously assessed., Methods: A 16-week, prospective, randomized, multicenter, open-label study in PD subjects on stable levodopa/carbidopa (LC) doses with EODWO. The IS subjects switched to LCE at baseline; DEL subjects at week 4. The primary efficacy variable was UPDRS III score (baseline to week 4). QoL measurements (PDQUALIF, PDQ-39) were assessed at baseline, weeks 4, 8, and study endpoint., Results: The intent-to-treat population comprised 350/359 patients (IS, n = 177; DEL, n = 173). A significant decrease in UPDRS III scores at week 4 was observed (IS, 3.7U, p < .0001; DEL, 1.8U, p = .0018). Group differences favored IS (1.9U, p = .0148). At week 8, IS subjects had significant total score decreases in PDQUALIF (2.5U, p = .0133) and PDQ-39 (5.8U, p = .0001). In the mobility and activities of daily living PDQ-39 subdomains, IS subjects had significantly larger week 4 decreases (versus DEL p = .0331 and p = .0125, respectively). Adverse events included diarrhea (14.5%), nausea (12.3%), and dizziness (8.4%)., Conclusion: The IS provided greater motor improvement at week 4 and improved QoL at week 8.

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., (© 2010 Blackwell Publishing Ltd.)

Objective: L-dopa is the most widely used and most effective therapy for Parkinson disease (PD), but chronic treatment is associated with motor complications in the majority of patients. It has been hypothesized that providing more continuous delivery of L-dopa to the brain would reduce the risk of motor complications, and that this might be accomplished by combining L-dopa with entacapone, an inhibitor of catechol-O-methyltransferase, to extend its elimination half-life., Methods: We performed a prospective 134-week double-blind trial comparing the risk of developing dyskinesia in 747 PD patients randomized to initiate L-dopa therapy with L-dopa/carbidopa (LC) or L-dopa/carbidopa/entacapone (LCE), administered 4x daily at 3.5-hour intervals. The primary endpoint was time to onset of dyskinesia., Results: In comparison to LC, patients receiving LCE had a shorter time to onset of dyskinesia (hazard ratio, 1.29; p = 0.04) and increased frequency at week 134 (42% vs 32%; p = 0.02). These effects were more pronounced in patients receiving dopamine agonists at baseline. Time to wearing off and motor scores were not significantly different, but trended in favor of LCE treatment. Patients in the LCE group received greater L-dopa dose equivalents than LC-treated patients (p < 0.001)., Interpretation: Initiating L-dopa therapy with LCE failed to delay the time of onset or reduce the frequency of dyskinesia compared to LC. In fact, LCE was associated with a shorter time to onset and increased frequency of dyskinesia compared to LC. These results may reflect that the treatment protocol employed did not provide continuous L-dopa availability and the higher L-dopa dose equivalents in the LCE group.

Background: Observational studies suggest that single-tablet formulations are associated with improved adherence versus the same components taken as separate tablets. The objective of this study was to compare adherence in patients with Parkinson's disease (PD) receiving levodopa therapy as levodopa/carbidopa/entacapone tablets (LCE) versus levodopa/carbidopa (LC) tablets and entacapone (E) as separate tablets (LC and E)., Methods: This was a retrospective, observational cohort study using a large health insurance claims database. Subjects included persons with a PD diagnosis who were receiving LC without E and then received either an add-on therapy with E as a separate tablet (LC and E) or LCE as one tablet (LCE). The primary study outcome was treatment adherence, estimated from pharmacy refills based on the 'percent of days covered' (PDC) with LCE or LC and E during follow-up and compared for patients receiving LCE and LC and E using multivariate regression analyses., Results: In multivariate analyses controlling for differences between groups in baseline characteristics, including pre-index dosage of and adherence with LC, receipt of LCE (n = 388) was associated with 79% lower mean non-adherence during follow-up (95% CI: 73-83%; p < 0.001) versus LC and E (n = 823), 86% lower odds of unsatisfactory adherence (95% CI: 80-91%; p < 0.001), and a 26% lower risk of discontinuation (95% CI: 6-42%; p < 0.013)., Limitations: This was an observational study with the inherent potential for selection bias. Pharmacy claims may not provide an accurate estimate of adherence. Requiring subjects to have a certain number of prescriptions before and after the index date may yield a sample that is not representative of all patients initiating levodopa therapy in typical clinical practice., Conclusions: Better adherence with LCE may have important implications for maintaining function in patients receiving chronic oral levodopa therapy. Further research is needed to confirm these results and examine the association between improved adherence and clinical and economic outcomes.

6-gingerol, a major component of ginger, has antioxidant, anti-apoptotic, and anti-inflammatory activities. However, some dietary phytochemicals possess pro-oxidant effects as well, and the risk of adverse effects is increased by raising the use of doses. The aim of this study was to assess the genotoxic effects of 6-gingerol and to clarify the mechanisms, using human hepatoma G2 (HepG2) cells. Exposure of the cells to 6-gingerol caused significant increase of DNA migration in comet assay, increase of micronuclei frequencies at high concentrations at 20-80 and 20-40 microM, respectively. These results indicate that 6-gingerol caused DNA strand breaks and chromosome damage. To further elucidate the underlying mechanisms, we tested lysosomal membrane stability, mitochondrial membrane potential, the intracellular generation of reactive oxygen species (ROS) and reduced glutathione (GSH). In addition, the level of oxidative DNA damage was evaluated by immunocytochemical analysis on 8-hydroxydeoxyguanosine (8-OHdG). Results showed that lysosomal membrane stability was reduced after treatment by 6-gingerol (20-80 microM) for 40 min, mitochondrial membrane potential decreased after treatment for 50 min, GSH and ROS levels were significantly increased after treatment for 60 min. These suggest 6-gingerol induces genotoxicity probably by oxidative stress; lysosomal and mitochondrial damage were observed in 6-gingerol-induced toxicity., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)