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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Long-Term Efficacy and Safety of Pimecrolimus Cream 1% in Adults with Moderate Atopic Dermatitis

Meurer, Michael, Fartasch, Manige, Albrecht, Gisela, Vogt, Thomas, Worm, Margitta, Ruzicka, Thomas, Altmeyer, Peter Josef, Schneider, Dirk, Weidinger, Gottfried, Bräutigam, Matthias 28 February 2014 (has links) (PDF)
Background: Pimecrolimus cream 1% is a non-steroid, selective inflammatory cytokine inhibitor indicated for atopic dermatitis (AD). Objective: To compare the safety and efficacy of pimecrolimus cream 1%-based treatment versus conventional therapy in adults with moderate AD. Methods: Patients were randomized to receive pimecrolimus cream 1% (n = 62) or vehicle (n = 68) at the first signs/symptoms of AD, for 24 weeks as required. A moderately potent topical corticosteroid (prednicarbate 0.25% cream) was allowed in both groups to treat flares. Results: Corticosteroids were required on fewer days in the pimecrolimus group, compared with the vehicle group (9.7 vs. 37.8%, p < 0.001). Furthermore, 59.7% of pimecrolimus-treated patients experienced no flares during the study period, compared with 22.1% of vehicle-treated patients (p < 0.001). Pimecrolimus cream 1% was well tolerated throughout the study. Conclusion: For adults with moderate AD, pimecrolimus cream 1% is well tolerated, reduces the incidence of flares, reduces/eliminates corticosteroid use, improves long-term disease control and enhances the patients’ quality of life. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
2

Treatment Following an Evidence-Based Algorithm versus Individualised Symptom-Oriented Treatment for Atopic Eczema

Schmitt, Jochen, Meurer, Michael, Schwanebeck, Uta, Grählert, Xina, Schäkel, Knut 28 February 2014 (has links) (PDF)
Background: Evidence-based treatment algorithms, successfully established for asthma, are missing for atopic eczema (AE). Objectives: To investigate whether treatment according to an evidence-based algorithm is an effective and applicable concept for the management of AE. Methods: Based on a systematic literature review, we developed an evidence-based severity-score-oriented treatment algorithm for AE and compared its effectiveness to that of an individualised symptom-oriented treatment (individual therapy) in a randomised controlled trial. Sixty-three participants were randomised to algorithm (n = 32) or individual therapy (n = 31) and treated accordingly for 12 months. Study end points included difference between baseline SCORAD and mean SCORAD under treatment (primary end point), quality of life and treatment utilisation. Analysis was by intention to treat (registration: ClinicalTrials.gov:NCT00148746). Results: No statistically significant differences in clinical or subjective response were observed between groups. Treatment following the algorithm and individual treatment both effectively controlled AE. Mean SCORAD reductions were 47% (95% confidence interval, CI = 38–55; algorithm) and 42% (95% CI = 29–54; individual). Clinical response was paralleled by improved quality of life in both groups. Physicians adhered to the algorithm option in 93% of their treatment decisions. Conclusion: Treatment following an evidence-based algorithm is an effective and applicable concept for the management of AE but does not show clear advantages compared to individualised treatment in a dermatological setting. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
3

Pimecrolimus Cream in the Long-Term Management of Atopic Dermatitis in Adults: A Six-Month Study

Meurer, Michael, Fölster-Holst, Regina, Wozel, Gottfried, Weidinger , Gottfried, Jünger, Michael, Bräutigam, Matthias 28 February 2014 (has links) (PDF)
Background: Pimecrolimus cream (Elidel®, SDZ ASM 981), a non-steroid inhibitor of inflammatory cytokines, is effective in the treatment of atopic dermatitis (AD). We assessed whether early treatment of AD signs/symptoms reduces the need for topical corticosteroids. Objective: To investigate the efficacy and safety of pimecrolimus cream 1% in the long-term management of adult AD. Methods: 192 adults with moderate to severe AD were randomised (1:1) for twice daily (b.i.d.) treatment of early signs or symptoms of AD with either pimecrolimus cream 1% or vehicle cream (control group) to prevent progression to flares. Treatment was given as needed for 24 weeks. In the event of flares, a moderately potent corticosteroid (prednicarbate 0.25% cream) was permitted as rescue medication in both groups. The percentage of days on which a topical corticosteroid was used to treat disease flares was the main outcome measure. Results: Corticosteroid medication was used on 14.2% (95% confidence interval, CI: 8.3–21.1) of the days of the 24-week treatment period in the pimecrolimus group and on 37.2% (95% CI: 30.4–44.0) of the days in the control group (p < 0.001). In total, 44.8% (43/96) of patients in the pimecrolimus group did not experience a flare compared with 18.8% (18/96) of patients in the control group. The median time to first flare was 144 days in the pimecrolimus group and 26 days in the control group (p < 0.001). Pimecrolimus treatment was also associated with improvement in signs and symptoms of AD, pruritus, patients’ self-assessment and quality of life. Conclusions: Pimecrolimus cream 1% b.i.d. is an effective, well-tolerated, long-term treatment for AD in adults, substantially reducing the number of flares compared to a conventional therapy and consequently reducing or eliminating the need for corticosteroid treatment. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
4

New and alternative approaches to the assessment of pharmacokinetic and pharmacodynamic equivalence

Ozdin, Deniz 03 1900 (has links)
La bioéquivalence, une mesure de substitution de l'innocuité et de l'efficacité à différents stades du processus de développement des médicaments, est tout particulièrement importante lors du développement d'un médicament générique. Entre autres critères, la bioéquivalence garantit que les médicaments génériques sont équivalents aux produits innovateurs ou de références approuvés en termes d’efficacité clinique et d’innocuité tout en contournant le long cours et le coût élevé des essais chez les animaux et des essais cliniques chez les patients exigés pour les médicaments innovants. Malgré les avancées dans le développement d'approches robustes au cours des dernières décennies, la pratique actuelle de la bioéquivalence fait toujours l'objet de controverses. Le but de cette thèse est d'explorer certaines de ces controverses et de les aborder en proposant des approches nouvelles et alternatives. L'une des questions les plus controversées dans la pratique actuelle de la bioéquivalence est l'extrapolation des résultats d'études de bioéquivalence d'une population à une autre. La majorité des études de bioéquivalence portant sur des formes pharmaceutiques orales efficaces par voie systémique reposent sur les critères de pharmacocinétique obtenus chez des sujets sains, alors que la population cible est constituée de patients. Ceci est basé sur l'hypothèse que si deux produits sont bioéquivalents dans une population, ils devraient l'être dans une autre. L'extrapolation des résultats des études de bioéquivalence ne se limite pas à celle des sujets sains aux patients. Depuis 2007, une proportion croissante d'études de bioéquivalence pharmacocinétique portant sur des soumissions génériques nord-américaines ou européennes a été réalisée auprès de populations géographiques/ethniques autres que celles visées, en raison du coût moins élevé de ces études en dehors de l'Amérique du Nord et de l'Europe. Dans le premier volet de cette thèse, nous avons examiné si les résultats de la bioéquivalence obtenus dans une population géographique ou ethnique pouvaient être extrapolés à une autre. À cette fin, nous avons extrait les résultats des études de bioéquivalence pharmacocinétique disponibles publiquement et provenant de soumissions génériques à Santé Canada et à la Food and Drug Administration des États-Unis. Pour dix médicaments différents, nous avons calculé l'effet d’un repas normalisé sur le produit de référence et comparé les résultats obtenus chez deux populations ethniques, les indiens et les nord-américains. Cette approche novatrice est basée sur le raisonnement suivant: si l'effet d’un repas sur le produit de référence est le même chez les populations indienne et nord-américaine, le produit générique et sa référence qui se sont révélés bioéquivalents dans la population indienne devraient également l'être dans la population nord-américaine. Pour 90% des médicaments à l'étude, une différence statistiquement significative a été détectée entre les deux populations après un repas. Pour 30% de ces médicaments, la différence s'est révélée d'une pertinence clinique possible. Les résultats de cette étude ont mis en évidence que l’extrapolation des résultats de bioéquivalence d’une population à l’autre devrait possiblement être reconsidérée pour certains médicaments. Les défis dans le contexte de la bioéquivalence ne se limitent pas toujours aux études pivots où la performance d’un produit générique est comparée à celle de la référence. En effet, une étude pilote peut être menée afin d’établir un protocole d’étude approprié pour cette étude pivot. Par conséquent, les résultats inexacts provenant d'une étude pilote, tels qu'une estimation imprécise du moment ou de la durée d’administration optimale de la dose lors de la comparaison du produit testé par rapport à la référence, pourront affecter négativement les résultats de l’étude de bioéquivalence. Ceci est particulièrement crucial pour les produits indiqués pour un usage topique dermatologique dont les corticostéroïdes constituent un cas d’espèce. En effet, leur bioéquivalence est démontrée par une mesure pharmacodynamique, le blanchiment cutané, à différents temps après application topique. L’intensité du blanchiment est comparée entre le produit générique et le produit de référence à une durée d’administration spécifique d’une dose donnée, la DD50, soit la durée associée à 50% de l’effet maximal observé. Par conséquent, cette durée d’administration de la dose doit d’abord être déterminée dans le cadre d’une étude pilote. L’agence réglementaire américaine recommande l’utilisation d’une approche populationnelle basée sur la modélisation non linéaire à effets mixtes pour l'estimation de la DD50 et ce, quelle que soit la méthode d'analyse. Étant donné qu’il existe différents types de méthodes d’analyse non linéaire à effets mixtes, chaque commanditaire peut en choisir une différente. Dans le deuxième volet de cette thèse, nous avons examiné si les mêmes estimations de DD50 pouvaient être obtenues en utilisant différentes méthodes non linéaires à effets mixtes. À cette fin, nous avons ajusté les données de blanchiment de la peau d’onze études avec deux méthodes non linéaires à effets mixtes différentes : le maximum de vraisemblance avec maximisation de l’espérance (MLEM) et l'estimation conditionnelle de premier ordre (FOCE). Les résultats ont favorisé MLEM, compte tenu d’une meilleure puissance discriminative pour l’estimation de la DD50 de population et d’une meilleure minimisation de la variabilité interindividuelle. Bien que l'approche de la bioéquivalence fondée sur la pharmacocinétique ait contribuée de manière significative au développement de versions génériques de haute qualité des formes pharmaceutiques orales indiquées pour un effet systémique, la disponibilité de versions génériques pour les produits dermatologiques topiques demeure limitée et ce, par manque de méthodes acceptées par les agences réglementaires pour l'évaluation de la bioéquivalence de ces produits. Dans le troisième volet de cette thèse, une nouvelle approche pour l’évaluation de la bioéquivalence de formulations de crème topique d’acyclovir a été développée en utilisant une analyse basée sur un modèle de données d’exposition locales récupérées à partir d’échantillons de peau abrasée prélevés à une seule durée d’administration de la dose, la DD50 à l’aide de bandes adhésives. Un seul échantillonnage de peau effectué à la DD50 a non seulement assuré que les données pharmacocinétiques étaient recueillies à la durée d’administration de la dose ayant le meilleur pouvoir discriminant pour détecter une différence au niveau des formulations, mais a également permis de diminuer considérablement le nombre d'échantillons à analyser. Et surtout, cette nouvelle approche a permis de générer un profil pharmacocinétique au niveau même de la peau. Ce faisant, nous avons pu utiliser l'analyse compartimentale populationnelle et contourner les nombreuses hypothèses et calculs sophistiqués requis par les méthodes précédentes. Notre approche a également permis de générer de nouveaux paramètres pharmacocinétiques permettant de décrire la vitesse et le degré d’exposition cutanée pour l'évaluation de la biodisponibilité et de la bioéquivalence topiques. Finalement, cette méthode a le potentiel de discerner une formulation bioéquivalente d’une autre qui ne l’est pas. / Bioequivalence is a surrogate measure of safety and efficacy in different stages of drug development process with the most pronounced significance in the development of generic drugs. Bioequivalence, among other standards, ensures that generic drugs are equivalent to their approved innovator or reference products in terms of clinical efficacy and safety while circumventing the lengthy-time course and high cost of animal and clinical trials in patients required for innovator drugs. Despite the advancements in development of robust bioequivalence approaches over the past decades, there are still controversies in the current practice of bioequivalence. The aim of this thesis is to explore some of these controversies and address them by putting forward new and alternative approaches. One of the most controversial issues in the current practice of bioequivalence is the extrapolation of bioequivalence study results from one population to another. The majority of bioequivalence studies for systemic effective oral dosage forms are conducted based on pharmacokinetic endpoints in healthy volunteers whilst the targeted population is patients. This is based on the assumption that if two products are bioequivalent in one population, they should be bioequivalent in another one. The extrapolation of bioequivalence study results is not limited to that from healthy volunteers to patients. Since 2007, an ever-increasing proportion of pharmacokinetic bioequivalence studies for North American or European generic submissions have been performed in geographical/ethnic populations other than the intended ones, due to the lower cost of these studies outside North America and Europe. In the first part of this thesis, we investigated whether the bioequivalence results obtained in one geographical or ethnic population can be extrapolated to another one. To this purpose, we extracted pharmacokinetic bioequivalence studies results from generic submissions to Health Canada and the US Food and Drug Administration. We calculated food effect for ten different reference drug products and compared the results for each product between two ethnic populations, Indians and North Americans. This is based on the reasoning that if food effect is found to be the same between the Indian and North American populations, then the generic product and its reference that were found to be bioequivalent in the Indian population should also be bioequivalent in North American population. For 90% of the study drugs, statistically significant difference was detected in the food effect between two populations. For 30% of these drugs, the difference was found to be of possible clinical relevance. The results of this study raised a flag for extrapolating the bioequivalence results from one population to another. Challenges in the context of bioequivalence are not always limited to the pivotal studies where the performance of a generic product is compared to that of Reference. Prior to pivotal bioequivalence studies, a pilot study may be conducted to establish an appropriate study design for the pivotal bioequivalence study. Therefore, inaccurate results from a pilot study, such as inaccurate estimation of time point or dose duration for comparison of test versus reference, can affect the bioequivalence outcomes adversely. An example to this case is the comparison of the extent of skin blanching, the pharmacological effect of generic versus reference products of topical dermatological corticosteroids at specific dose duration, DD50, where the effect is half maximal. This dose duration should initially be determined in a pilot study. The US FDA 1995 Guidance document recommends the use of non-linear mixed effect population modeling for the estimation of DD50, irrespective of the method of analysis. Given the availability of different types of non-linear mixed effect modeling methods, each sponsor could choose a different one. In the second part of this thesis we investigated whether the same DD50 estimates can be obtained when different non-linear mixed effect modeling methods are used. To this purpose, we fitted the skin blanching data from eleven studies with two different non-linear mixed effect modeling methods, the Maximum Likelihood Expectation Maximization (MLEM) and the First Order Conditional Estimation (FOCE). The results favored MLEM given its lower population DD50 estimates that would locate in a more discriminative portion of the Emax curve and better minimization of inter-individual variability. Although the pharmacokinetic-based bioequivalence approach has contributed significantly to the development of high-quality generic versions of systemic effective oral dosage form, the availability of generic versions of topical dermatological products remains constrained due to the limited methods accepted for bioequivalence evaluation of these products. In the third part of this thesis, a novel approach for the bioequivalence assessment of topical acyclovir cream formulations was developed based on the model-based analysis of local exposure data recovered from tape stripping of the skin at a single dose duration, DD50. Conducting the stripping procedure only at DD50 not only ensured that the PK data was collected at the dose duration that is most discriminative of formulation differences, but it also decreased the number of samples to be analyzed significantly. More importantly, our novel approach in generating the local PK profile in the skin (dermatopharmacokinetic profile) and the implementation of population compartmental analysis circumvented the numerous assumptions and sophisticated calculations that were inherent to previous methods, while yielding the PK parameters relevant for topical bioavailability and bioequivalence assessment (rate and extent of exposure to the skin). This method successfully concluded bioequivalence and its absence.
5

Treatment Following an Evidence-Based Algorithm versus Individualised Symptom-Oriented Treatment for Atopic Eczema: A Randomised Controlled Trial

Schmitt, Jochen, Meurer, Michael, Schwanebeck, Uta, Grählert, Xina, Schäkel, Knut January 2008 (has links)
Background: Evidence-based treatment algorithms, successfully established for asthma, are missing for atopic eczema (AE). Objectives: To investigate whether treatment according to an evidence-based algorithm is an effective and applicable concept for the management of AE. Methods: Based on a systematic literature review, we developed an evidence-based severity-score-oriented treatment algorithm for AE and compared its effectiveness to that of an individualised symptom-oriented treatment (individual therapy) in a randomised controlled trial. Sixty-three participants were randomised to algorithm (n = 32) or individual therapy (n = 31) and treated accordingly for 12 months. Study end points included difference between baseline SCORAD and mean SCORAD under treatment (primary end point), quality of life and treatment utilisation. Analysis was by intention to treat (registration: ClinicalTrials.gov:NCT00148746). Results: No statistically significant differences in clinical or subjective response were observed between groups. Treatment following the algorithm and individual treatment both effectively controlled AE. Mean SCORAD reductions were 47% (95% confidence interval, CI = 38–55; algorithm) and 42% (95% CI = 29–54; individual). Clinical response was paralleled by improved quality of life in both groups. Physicians adhered to the algorithm option in 93% of their treatment decisions. Conclusion: Treatment following an evidence-based algorithm is an effective and applicable concept for the management of AE but does not show clear advantages compared to individualised treatment in a dermatological setting. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
6

Long-Term Efficacy and Safety of Pimecrolimus Cream 1% in Adults with Moderate Atopic Dermatitis

Meurer, Michael, Fartasch, Manige, Albrecht, Gisela, Vogt, Thomas, Worm, Margitta, Ruzicka, Thomas, Altmeyer, Peter Josef, Schneider, Dirk, Weidinger, Gottfried, Bräutigam, Matthias January 2004 (has links)
Background: Pimecrolimus cream 1% is a non-steroid, selective inflammatory cytokine inhibitor indicated for atopic dermatitis (AD). Objective: To compare the safety and efficacy of pimecrolimus cream 1%-based treatment versus conventional therapy in adults with moderate AD. Methods: Patients were randomized to receive pimecrolimus cream 1% (n = 62) or vehicle (n = 68) at the first signs/symptoms of AD, for 24 weeks as required. A moderately potent topical corticosteroid (prednicarbate 0.25% cream) was allowed in both groups to treat flares. Results: Corticosteroids were required on fewer days in the pimecrolimus group, compared with the vehicle group (9.7 vs. 37.8%, p < 0.001). Furthermore, 59.7% of pimecrolimus-treated patients experienced no flares during the study period, compared with 22.1% of vehicle-treated patients (p < 0.001). Pimecrolimus cream 1% was well tolerated throughout the study. Conclusion: For adults with moderate AD, pimecrolimus cream 1% is well tolerated, reduces the incidence of flares, reduces/eliminates corticosteroid use, improves long-term disease control and enhances the patients’ quality of life. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
7

Pimecrolimus Cream in the Long-Term Management of Atopic Dermatitis in Adults: A Six-Month Study

Meurer, Michael, Fölster-Holst, Regina, Wozel, Gottfried, Weidinger, Gottfried, Jünger, Michael, Bräutigam, Matthias January 2002 (has links)
Background: Pimecrolimus cream (Elidel®, SDZ ASM 981), a non-steroid inhibitor of inflammatory cytokines, is effective in the treatment of atopic dermatitis (AD). We assessed whether early treatment of AD signs/symptoms reduces the need for topical corticosteroids. Objective: To investigate the efficacy and safety of pimecrolimus cream 1% in the long-term management of adult AD. Methods: 192 adults with moderate to severe AD were randomised (1:1) for twice daily (b.i.d.) treatment of early signs or symptoms of AD with either pimecrolimus cream 1% or vehicle cream (control group) to prevent progression to flares. Treatment was given as needed for 24 weeks. In the event of flares, a moderately potent corticosteroid (prednicarbate 0.25% cream) was permitted as rescue medication in both groups. The percentage of days on which a topical corticosteroid was used to treat disease flares was the main outcome measure. Results: Corticosteroid medication was used on 14.2% (95% confidence interval, CI: 8.3–21.1) of the days of the 24-week treatment period in the pimecrolimus group and on 37.2% (95% CI: 30.4–44.0) of the days in the control group (p < 0.001). In total, 44.8% (43/96) of patients in the pimecrolimus group did not experience a flare compared with 18.8% (18/96) of patients in the control group. The median time to first flare was 144 days in the pimecrolimus group and 26 days in the control group (p < 0.001). Pimecrolimus treatment was also associated with improvement in signs and symptoms of AD, pruritus, patients’ self-assessment and quality of life. Conclusions: Pimecrolimus cream 1% b.i.d. is an effective, well-tolerated, long-term treatment for AD in adults, substantially reducing the number of flares compared to a conventional therapy and consequently reducing or eliminating the need for corticosteroid treatment. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

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