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Ian A. Dubery - One of the best experts on this subject based on the ideXlab platform.
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Similar, but different: structurally related Azelaic Acid and hexanoic Acid trigger differential metabolomic and transcriptomic responses in tobacco cells
BMC Plant Biology, 2017Co-Authors: Arnaud T. Djami-tchatchou, Efficient N. Ncube, Paul A. Steenkamp, Ian A. DuberyAbstract:BackgroundPlants respond to various stress stimuli by activating an enhanced broad-spectrum defensive ability. The development of novel resistance inducers represents an attractive, alternative crop protection strategy. In this regard, hexanoic Acid (Hxa, a chemical elicitor) and Azelaic Acid (Aza, a natural signaling compound) have been proposed as inducers of plant defense, by means of a priming mechanism. Here, we investigated both the mode of action and the complementarity of Aza and Hxa as priming agents in Nicotiana tabacum cells in support of enhanced defense.ResultsMetabolomic analyses identified signatory biomarkers involved in the establishment of a pre-conditioned state following Aza and Hxa treatment. Both inducers affected the metabolomes in a similar manner and generated common biomarkers: caffeoylputrescine glycoside, cis-5-caffeoylquinic Acid, feruloylglycoside, feruloyl-3-methoxytyramine glycoside and feruloyl-3-methoxytyramine conjugate. Subsequently, quantitative real time-PCR was used to investigate the expression of inducible defense response genes: phenylalanine ammonia lyase, hydroxycinnamoyl CoA quinate transferase and hydroxycinnamoyl transferase to monitor activation of the early phenylpropanoid pathway and chlorogenic Acids metabolism, while ethylene response element-binding protein, small sar1 GTPase, heat shock protein 90, RAR1, SGT1, non-expressor of PR genes 1 and thioredoxin were analyzed to report on signal transduction events. Pathogenesis-related protein 1a and defensin were quantified to investigate the activation of defenses regulated by salicylic Acid and jasmonic Acid respectively. The qPCR results revealed differential expression kinetics and, in general (except for NPR1, Thionin and PR1a), the relative gene expression ratios observed in the Hxa-treated cells were significantly greater than the expression observed in the cells treated with Aza.ConclusionsThe results indicate that Aza and Hxa have a similar priming effect through activation of genes involved in the establishment of systemic acquired resistance, associated with enhanced synthesis of hydroxycinnamic Acids and related conjugates.
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similar but different structurally related Azelaic Acid and hexanoic Acid trigger differential metabolomic and transcriptomic responses in tobacco cells
BMC Plant Biology, 2017Co-Authors: Arnaud T Djamitchatchou, Paul A. Steenkamp, Efficient N. Ncube, Ian A. DuberyAbstract:Plants respond to various stress stimuli by activating an enhanced broad-spectrum defensive ability. The development of novel resistance inducers represents an attractive, alternative crop protection strategy. In this regard, hexanoic Acid (Hxa, a chemical elicitor) and Azelaic Acid (Aza, a natural signaling compound) have been proposed as inducers of plant defense, by means of a priming mechanism. Here, we investigated both the mode of action and the complementarity of Aza and Hxa as priming agents in Nicotiana tabacum cells in support of enhanced defense. Metabolomic analyses identified signatory biomarkers involved in the establishment of a pre-conditioned state following Aza and Hxa treatment. Both inducers affected the metabolomes in a similar manner and generated common biomarkers: caffeoylputrescine glycoside, cis-5-caffeoylquinic Acid, feruloylglycoside, feruloyl-3-methoxytyramine glycoside and feruloyl-3-methoxytyramine conjugate. Subsequently, quantitative real time-PCR was used to investigate the expression of inducible defense response genes: phenylalanine ammonia lyase, hydroxycinnamoyl CoA quinate transferase and hydroxycinnamoyl transferase to monitor activation of the early phenylpropanoid pathway and chlorogenic Acids metabolism, while ethylene response element-binding protein, small sar1 GTPase, heat shock protein 90, RAR1, SGT1, non-expressor of PR genes 1 and thioredoxin were analyzed to report on signal transduction events. Pathogenesis-related protein 1a and defensin were quantified to investigate the activation of defenses regulated by salicylic Acid and jasmonic Acid respectively. The qPCR results revealed differential expression kinetics and, in general (except for NPR1, Thionin and PR1a), the relative gene expression ratios observed in the Hxa-treated cells were significantly greater than the expression observed in the cells treated with Aza. The results indicate that Aza and Hxa have a similar priming effect through activation of genes involved in the establishment of systemic acquired resistance, associated with enhanced synthesis of hydroxycinnamic Acids and related conjugates.
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Additional file 3: Figure S3. of Similar, but different: structurally related Azelaic Acid and hexanoic Acid trigger differential metabolomic and transcriptomic responses in tobacco cells
2017Co-Authors: Arnaud T. Djami-tchatchou, Efficient Ncube, Paul Steenkamp, Ian A. DuberyAbstract:Structures of annotated biomarkers: (1) caffeoylputrescine glycoside, (2) cis-5-caffeoylquinic Acid, (3) feruloylglycoside, (4) Azelaic Acid glycoside, (5) feruloyl-3-methyltyramine glycoside, (6) feruloyl-3-methyltyramine conjugate and (7) feruloyl-3-methyltyramine. (TIFF 25 kb
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Additional file 1: Figure S1. of Similar, but different: structurally related Azelaic Acid and hexanoic Acid trigger differential metabolomic and transcriptomic responses in tobacco cells
2017Co-Authors: Arnaud T. Djami-tchatchou, Efficient Ncube, Paul Steenkamp, Ian A. DuberyAbstract:UHPLC-MS (ESI negative) base peak intensity (BPI) chromatograms of Azelaic Acid-treated Nicotiana tabacum cell extracts at 24 h (a), 12 h (b), 6 h (c) and 0 h (d) post-treatment. The most intense peaks at a specific retention time (Rt) are indicated with m/z values. (TIFF 84 kb
James Q Del Rosso - One of the best experts on this subject based on the ideXlab platform.
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cathelicidin kallikrein 5 and serine protease activity is inhibited during treatment of rosacea with Azelaic Acid 15 gel
Journal of The American Academy of Dermatology, 2013Co-Authors: Alvin B Coda, Julie C Harper, Tissa Hata, Jeremiah Miller, David Audish, Paul Kotol, Aimee M Two, Faiza Shafiq, Kenshi Yamasaki, James Q Del RossoAbstract:Background Excess cathelicidin and kallikrein 5 (KLK5) have been hypothesized to play a role in the pathophysiology of rosacea. Objective We sought to evaluate the effects of Azelaic Acid (AzA) on these elements of the innate immune system. Methods Gene expression and protease activity were measured in laboratory models and patients with rosacea during a 16-week multicenter, prospective, open-label study of 15% AzA gel. Results AzA directly inhibited KLK5 in cultured keratinocytes and gene expression of KLK5, Toll-like receptor-2, and cathelicidin in mouse skin. Patients with rosacea showed reduction in cathelicidin and KLK5 messenger RNA after treatment with AzA gel. Subjects without rosacea had lower serine protease activity (SPA) than patients with rosacea. Distinct subsets of patients with rosacea who had high and low baseline SPA were identified, and patients with high baseline exhibited a statistically significant reduction of SPA with 15% AzA gel treatment. Limitations Study size was insufficient to predict clinical efficacy based on the innate immune response to AzA. Conclusions These results show that cathelicidin and KLK5 decrease in association with AZA exposure. Our observations suggest a new mechanism of action for AzA and that SPA may be a useful biomarker for disease activity.
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Azelaic Acid gel 15 in the management of papulopustular rosacea a status report on available efficacy data and clinical application
Cutis, 2011Co-Authors: James Q Del Rosso, Neal BhatiaAbstract:Azelaic Acid (AzA) gel 15% is approved by the US Food and Drug Administration (FDA) for the treatment of papulopustular rosacea (PPR). Its efficacy and safety as monotherapy have been demonstrated. Release of active drug from the gel formulation is superior to the cream. The combination of AzA gel 15% with oral doxycycline appears to expedite and augment response, especially in cases of PPR of greater severity, and AzA gel 15% maintains control of PPR over 6 months as compared to vehicle. Adjunctive skin care is recommended to augment the therapeutic outcome of PPR and reduce the potential for irritation that can occur with topical therapy.
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efficacy of topical Azelaic Acid aza gel 15 plus oral doxycycline 40 mg versus metronidazole gel 1 plus oral doxycycline 40 mg in mild to moderate papulopustular rosacea
Journal of Drugs in Dermatology, 2010Co-Authors: James Q Del Rosso, Suzanne Bruce, Michael Jarratt, Alan Menter, Gerald StaedtlerAbstract:Rosacea is a leading reason why people seek the care of a dermatologist, accounting for nearly 7 million office visits annually. Pharmacologic treatments include both topical and oral medications, which are increasingly being used in combination, especially at the outset of therapy. This exploratory study assesses the safety, effectiveness and speed of onset of two common topical agents for the treatment of rosacea--Azelaic Acid gel (AzA) 15% and metronidazole gel 1%--used in conjunction with anti-inflammatory dose doxycycline (40 mg once daily). Men and women (n = 207) with mild-to-moderate papulopustular rosacea were enrolled and randomized to receive either AzA gel 15% twice daily plus doxycycline 40 mg once daily (AzA group) or metronidazole gel 1% once daily plus doxycycline 40 mg once daily (Metro group) for 12 weeks. Both regimens were safe, efficacious and well tolerated. Efficacy parameters revealed a possible trend toward greater and earlier benefit with the AzA-based regimen than with the metronidazole-based regimen. These findings warrant further investigation in a sufficiently powered study.
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Azelaic Acid 15 gel once daily versus twice daily in papulopustular rosacea
Journal of Drugs in Dermatology, 2008Co-Authors: Diane Thiboutot, Alan B Fleischer, James Q Del Rosso, Klaus GraupeAbstract:Background: Twice-daily Azelaic Acid (AzA) is the conventional regimen for papulopustular rosacea, but once-daily AzA may be equally effective, with greater convenience and dosing flexibility. In order to test this hypothesis, an exploratory study was conducted. Methods: The evaluable efficacy population of this 12-week double-blind, parallel-group study included 72 patients and the population that was used to report safety results included 92 patients. Baseline characteristics were comparable between the once-daily and twice-daily study groups. Evaluations were performed at baseline and at weeks 4, 8, and 12. Results: No significant difference was found between the once-daily and twice-daily groups at the end of study therapy in mean investigator global assessment (IGA) scores, treatment success, or treatment response. The mean number of inflammatory lesions, the intensity of erythema intensity, and the intensity of telangiectasia at treatment end were likewise not significantly different (P>.205 for all). More than 90% of subjects in each group rated cosmetic acceptability of this AzA gel as satisfactory or better. Conclusion: Based on these findings and those of prior studies, once-daily AzA 15% gel can therefore be utilized as a safe, effective, and economical dosing option for the treatment of mild-to-moderate papulopustular rosacea. Once-daily dosing of AzA 15% gel was well accepted by patients and can offer considerable dosing flexibility and convenience for the patient as well as for the dermatologist.
Klaus Graupe - One of the best experts on this subject based on the ideXlab platform.
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Azelaic Acid 15 gel once daily versus twice daily in papulopustular rosacea
Journal of Drugs in Dermatology, 2008Co-Authors: Diane Thiboutot, Alan B Fleischer, James Q Del Rosso, Klaus GraupeAbstract:Background: Twice-daily Azelaic Acid (AzA) is the conventional regimen for papulopustular rosacea, but once-daily AzA may be equally effective, with greater convenience and dosing flexibility. In order to test this hypothesis, an exploratory study was conducted. Methods: The evaluable efficacy population of this 12-week double-blind, parallel-group study included 72 patients and the population that was used to report safety results included 92 patients. Baseline characteristics were comparable between the once-daily and twice-daily study groups. Evaluations were performed at baseline and at weeks 4, 8, and 12. Results: No significant difference was found between the once-daily and twice-daily groups at the end of study therapy in mean investigator global assessment (IGA) scores, treatment success, or treatment response. The mean number of inflammatory lesions, the intensity of erythema intensity, and the intensity of telangiectasia at treatment end were likewise not significantly different (P>.205 for all). More than 90% of subjects in each group rated cosmetic acceptability of this AzA gel as satisfactory or better. Conclusion: Based on these findings and those of prior studies, once-daily AzA 15% gel can therefore be utilized as a safe, effective, and economical dosing option for the treatment of mild-to-moderate papulopustular rosacea. Once-daily dosing of AzA 15% gel was well accepted by patients and can offer considerable dosing flexibility and convenience for the patient as well as for the dermatologist.
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efficacy and safety of Azelaic Acid 15 gel as a new treatment for papulopustular rosacea results from two vehicle controlled randomized phase iii studies
Journal of The American Academy of Dermatology, 2003Co-Authors: Diane Thiboutot, Ruth Thieroffekerdt, Klaus GraupeAbstract:Abstract Background: Rosacea is a common, chronic dermatosis for which safe and effective new treatment options are needed. Objective: The objective of these studies was to evaluate the efficacy, tolerability, and safety of a new formulation of 15% Azelaic Acid (15%) gel (AzA gel), for the topical treatment of moderate, papulopustular rosacea. Methods: Two multicenter, double-blind, randomized, parallel-group, vehicle-controlled studies were conducted using identical study designs, patient-selection criteria, and efficacy end points. Overall, 329 patients were enrolled in study 1 and 335 patients in study 2. Results: Both studies consistently demonstrated the superiority of AzA gel over vehicle in the topical treatment of moderate, papulopustular rosacea. AzA gel yielded statistically significantly higher reductions in mean inflammatory lesion count than vehicle: 58% versus 40%, study 1 ( P = .0001); 51% versus 39%, study 2 ( P = .0208). Significantly higher proportions of patients treated with AzA gel experienced improvement in erythema compared with vehicle gel: 44% versus 29%, study 1 ( P = .0017); 46% versus 28%, study 2 ( P = .0005). Using the investigator's global assessment, therapeutic success in terms of a clear, minimal, or mild final result was achieved in 61% and 62% of patients treated with AzA gel in studies 1 and 2, respectively, which was significantly superior to the result achieved with vehicle (40% and 48%, respectively) ( P P = .0127, study 2). No serious, treatment-related adverse events were reported. Conclusion: The results of these 2 controlled studies demonstrate that AzA gel, used twice daily, is an efficacious, safe, and well-tolerated topical treatment for moderate, papulopustular rosacea. (J Am Acad Dermatol 2003;48:836-45.)
Antona J Wagstaff - One of the best experts on this subject based on the ideXlab platform.
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Azelaic Acid 15 gel in the treatment of papulopustular rosacea
American Journal of Clinical Dermatology, 2004Co-Authors: James E Frampton, Antona J WagstaffAbstract:Azelaic Acid is a naturally occurring, straight-chain dicarboxylic Acid which is effective in the treatment of rosacea, presumably on account of its anti-inflammatory properties. In randomized, double-blind, multicenter studies involving patients with moderate papulopustular facial rosacea, twice-daily topical application of Azelaic Acid 15% gel to the face was significantly more effective than twice-daily administration of either its vehicle (two studies) or metronidazole 0.75% gel (one study) in reducing inflammatory lesion counts and erythema severity. However, neither active treatment had a clinically discernable effect on telangiectasia. In all three studies, Azelaic Acid 15% gel recipients experienced continuous decreases in lesion counts and erythema throughout the 12- to 15-week treatment periods. However, the effects of metronidazole 0.75% gel plateauxed after 8 weeks. In other efficacy assessments in these studies, Azelaic Acid 15% gel was superior to its vehicle and metronidazole 0.75% gel in both the investigators’ global assessment of rosacea and the investigators’ end-of-study evaluation of overall improvement, and superior to its vehicle in the patients’ end-of-study evaluation of overall improvement. The most frequent treatment-related cutaneous adverse events during administration of Azelaic Acid 15% gel include burning/stinging/tingling and pruritus (itching); however, these events are predominantly transient in nature and mild-to-moderate in intensity.
Gerald Staedtler - One of the best experts on this subject based on the ideXlab platform.
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patient reported outcomes of Azelaic Acid foam 15 for patients with papulopustular rosacea secondary efficacy results from a randomized controlled double blind phase 3 trial
Cutis, 2016Co-Authors: Stephen K Tyring, Gerald Staedtler, Richard Nkulikiyinka, James A Solomon, Jason P Lott, Kaweh ShakeryAbstract:Patient-reported treatment outcomes are important for evaluating the impact of drug therapies on patient experience. A randomized, double-blind, vehicle-controlled, parallel-group, multicenter, phase 3 study was conducted in 961 participants to assess patient perception of efficacy, utility, and effect on quality of life (QOL) of an Azelaic Acid (AzA) 15% foam formulation for the treatment of papulopustular rosacea (PPR). Secondary end points included patient-reported global assessment of treatment response, global assessment of tolerability, and opinion on cosmetic acceptability and practicability of product use. Quality of life assessments included the Dermatology Quality of Life Index (DLQI) and Rosacea Quality of Life Index (RosaQOL). Self-reported global assessment of treatment response favored AzA foam over vehicle foam (P<.001), with 57.2% of the AzA foam group reporting excellent or good improvement versus 44.7% in the vehicle foam group. Tolerability was rated excellent or good in 67.8% of the AzA foam group versus 78.2% of the vehicle foam group. Mean overall DLQI scores at end of treatment (EoT) were improved (P=.018) in favor of the AzA foam group compared with the vehicle foam group. Both treatment groups showed improvements in RosaQOL. Treatment with AzA foam was associated with improved QOL and meaningful reductions in the patient-perceived burden of PPR, which correlates with earlier reported primary end points of this study and supports the inclusion of patient perspectives in studies evaluating the effects of topical dermatologic treatments.
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investigator reported efficacy of Azelaic Acid foam 15 in patients with papulopustular rosacea secondary efficacy outcomes from a randomized controlled double blind phase 3 trial
Cutis, 2016Co-Authors: James A Solomon, Meike Sand, Gerald Staedtler, Richard Nkulikiyinka, Stephen K Tyring, Kaweh ShakeryAbstract:Papulopustular rosacea (PPR) is characterized by centrofacial papules and pustules commonly associated with erythema. To compare investigator-reported efficacy outcomes for Azelaic Acid (AzA) foam 15% versus vehicle foam in PPR, a randomized, vehicle-controlled, double-blind phase 3 clinical trial was conducted at 48 US sites. Participants received AzA foam or vehicle foam for 12 weeks. Secondary efficacy outcomes included change in inflammatory lesion count (ILC), therapeutic response rate according to investigator global assessment (IGA), and change in erythema rating. This study was comprised of 961 participants with PPR. The results support the therapeutic superiority of AzA foam over vehicle foam.
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a phase 3 randomized double blind vehicle controlled trial of Azelaic Acid foam 15 in the treatment of papulopustular rosacea
Cutis, 2015Co-Authors: Zoe Diana Draelos, Boni E Elewski, Julie C Harper, Meike Sand, Gerald Staedtler, Richard Nkulikiyinka, Kaweh ShakeryAbstract:Rosacea is a chronic relapsing skin disorder primarily affecting the face. Although its etiology is not well defined, rosacea is associated with immune dysregulation and inflammation potentiated by external factors. These manifestations lead to skin sensitivity and impaired quality of life. Azelaic Acid (AzA) is approved for the treatment of rosacea in a 15% gel formulation. This phase 3 study evaluated the efficacy and safety of AzA in a 15% foam formulation for the treatment of papulopustular rosacea (PPR). Coprimary efficacy end points were treatment success according to investigator global assessment (IGA) and the nominal change in inflammatory lesion count (ILC) from baseline to the end of treatment (EoT). Adverse events (AEs) were evaluated as a measure of safety. The IGA success rate at EoT was significantly greater in the AzA foam group versus vehicle (P<.001; Cochran-Mantel-Haenszel test). Likewise, nominal ILC change at EoT in the AzA foam group showed a significantly greater decrease versus vehicle (P<.001; F test). Drug-related AEs were mainly mild to moderate, cutaneous, and local. Overall, the study results support the efficacy and safety of twice-daily AzA foam 15% in patients with PPR.
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Azelaic Acid foam 15 in the treatment of papulopustular rosacea a randomized double blind vehicle controlled study
Cutis, 2013Co-Authors: Zoe Diana Draelos, Boni E Elewski, Gerald Staedtler, Blanka HavlickovaAbstract:Rosacea is a common chronic inflammatory skin disease that primarily affects facial skin. Its etiology is unknown, and currently there is no cure. Rosacea can be associated with severe symptoms, including transient erythema (flushing), nontransient erythema, papules, pustules, and telangiectases, leading to substantial discomfort and an unattractive appearance. This randomized, double-blind, vehicle-controlled, multicenter, parallel-group study conducted over 12 weeks with a 4-week follow-up period evaluated the efficacy and safety of a new formulation of Azelaic Acid (AzA) foam in a 15% concentration compared to vehicle alone in patients with papulopustular rosacea (PPR). Primary efficacy variables assessed were investigator global assessment (IGA) dichotomized into success and failure, and nominal change in inflammatory lesion count from baseline to end of treatment. Results indicated that the new foam formulation of AzA is effective and well-tolerated in a population of patients with PPR. Although no single formulation is appropriate for all patients, the development of a new foam formulation in addition to other available vehicles provides patients with options and allows health care providers to match the needs as well as preferences of individual patients and skin types with appropriate delivery modalities.
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efficacy of topical Azelaic Acid aza gel 15 plus oral doxycycline 40 mg versus metronidazole gel 1 plus oral doxycycline 40 mg in mild to moderate papulopustular rosacea
Journal of Drugs in Dermatology, 2010Co-Authors: James Q Del Rosso, Suzanne Bruce, Michael Jarratt, Alan Menter, Gerald StaedtlerAbstract:Rosacea is a leading reason why people seek the care of a dermatologist, accounting for nearly 7 million office visits annually. Pharmacologic treatments include both topical and oral medications, which are increasingly being used in combination, especially at the outset of therapy. This exploratory study assesses the safety, effectiveness and speed of onset of two common topical agents for the treatment of rosacea--Azelaic Acid gel (AzA) 15% and metronidazole gel 1%--used in conjunction with anti-inflammatory dose doxycycline (40 mg once daily). Men and women (n = 207) with mild-to-moderate papulopustular rosacea were enrolled and randomized to receive either AzA gel 15% twice daily plus doxycycline 40 mg once daily (AzA group) or metronidazole gel 1% once daily plus doxycycline 40 mg once daily (Metro group) for 12 weeks. Both regimens were safe, efficacious and well tolerated. Efficacy parameters revealed a possible trend toward greater and earlier benefit with the AzA-based regimen than with the metronidazole-based regimen. These findings warrant further investigation in a sufficiently powered study.
