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Efferth T.,University of Mainz | Koch E.,Preclinical Research
Current Drug Targets | Year: 2011

Drugs derived from natural resources represent a significant segment of the pharmaceutical market as compared to randomly synthesized compounds. It is a goal of drug development programs to design selective ligands that act on single disease targets to obtain highly effective and safe drugs with low side effects. Although this strategy was successful for many new therapies, there is a marked decline in the number of new drugs introduced into clinical practice over the past decades. One reason for this failure may be due to the fact that the pathogenesis of many diseases is rather multi-factorial in nature and not due to a single cause. Phytotherapy, whose therapeutic efficacy is based on the combined action of a mixture of constituents, offers new treatment opportunities. Because of their biological defence function, plant secondary metabolites act by targeting and disrupting the cell membrane, by binding and inhibiting specific proteins or they adhere to or intercalate into RNA or DNA. Phytotherapeutics may exhibit pharmacological effects by the synergistic or antagonistic interaction of many phytochemicals. Mechanistic reasons for interactions are bioavailability, interference with cellular transport processes, activation of pro-drugs or deactivation of active compounds to inactive metabolites, action of synergistic partners at different points of the same signalling cascade (multi-target effects) or inhibition of binding to target proteins. "-Omics" technologies and systems biology may facilitate unravelling synergistic effects of herbal mixtures. © 2011 Bentham Science Publishers Ltd.

Rangel-Ordonez L.,Goethe University Frankfurt | Noldner M.,Preclinical Research | Schubert-Zsilavecz M.,Goethe University Frankfurt | Wurglics M.,Goethe University Frankfurt
Planta Medica | Year: 2010

It is undisputed that terpene lactones and flavonoid glycosides of Ginkgo biloba are responsible for most of the extracts (e.g., EGb 761®) pharmacological actions. This investigation focused on the pharmacokinetic and the ability of the flavonoid constituents to cross the blood-brain barrier in rats, after single (600mg/kg) or repeated (8 days, 100, or 600mg/kg) oral administration of EGb 761®, and their distribution in different areas of the brain. For this purpose, we developed an HPLC-fluorescence method for the determination of the Ginkgo flavonoid metabolites (quercetin, kaempferol, and isorhamnetin derivatives) in the brain and plasma. A single dose of 600mg/kg EGb 761® resulted in maximum plasma concentrations of 176, 341, and 183ng/mL for quercetin, kaempferol, and isorhamnetin/tamarixetin, respectively and in maximum brain concentrations of 291ng/g protein for kaempferol and 161ng/g protein for isorhamnetin/tamarixetin. In comparison, the repeated administration of the same dose for 8 days led to an approximate 4.5-fold increase in the plasma concentration for quercetin, 11.5-fold increase for kaempferol, and 10-fold increase for isorhamnetin/tamarixetin. In the brain, an approximate 2-fold increase was observed for kaempferol and isorhamnetin/tamarixetin. About 90% of the determined flavonoids were distributed in the hippocampus, frontal cortex, striatum, and cerebellum, which together represent only 38% of the whole brain. © Georg Thieme Verlag KG Stuttgart - New York.

Ude C.,Goethe University Frankfurt | Paulke A.,Goethe University Frankfurt | Noldner M.,Preclinical Research | Schubert-Zsilavecz M.,Goethe University Frankfurt | Wurglics M.,Goethe University Frankfurt
Planta Medica | Year: 2011

Several studies indicate that the terpene trilactones (TTL) of EGb 761® are responsible for most of its pharmacological action in the brain 1. Therefore, we investigated the ability of the TTL to cross the blood brain barrier in rats after a single oral administration (600 mg/kg) of EGb 761® and compared it with the plasma levels. In addition, we checked the pharmacokinetic characteristics of an application of EGb 761® against a similar amount of pure substances. For this purpose, we developed a sensitive HPLC-(APCI)-MS method for the determination of the Ginkgo biloba TTL (ginkgolide A [GA], B [GB], C [GC] and bilobalide [Bb]) in plasma as well as in brain tissue. The following animal study shows that the oral application of 600 mg/kg EGb 761® results in significant GA, GB, and Bb concentrations in plasma as well as in the CNS of the rodents, while the GC concentration was below the detection limit of the analytical method in both matrices. GA, GB, and Bb brain concentrations showed a rapid increase up to 55 ng/g, 40 ng/g, and 98 ng/g with no difference of the characteristic after extract or pure substance application. Regarding the plasma levels, significant higher Cmax and AUC values were detected after application of the extract EGb 761®. These results allow for the first time a discussion of pharmacological effects with the knowledge of the pharmacokinetic behavior of the TTL in target tissues. © Georg Thieme Verlag KG Stuttgart. New York.

Heintze S.D.,Preclinical Research | Ruffieux C.,University of Lausanne | Rousson V.,University of Lausanne
Dental Materials | Year: 2010

Objectives: To carry out a meta-analysis in order to assess the influencing factors on retention loss and marginal discoloration of cervical restorations made of composites and glass ionomer (derivates). Methods: The literature was searched for prospective clinical studies on cervical restorations with an observation period of at least 18 months. Results: Fifty clinical studies involving 40 adhesive systems matched the inclusion criteria. On average, 10% of the cervical fillings were lost and 24% exhibited marginal discoloration after 3 years. The variability ranged from 0% to 50% for retention loss and from 0% to 74% for marginal discoloration. Hardly any secondary caries was detected. When linear mixed models with a study and experiment effect were used, the analysis revealed that the adhesive/restorative class had the most significant influence, with 2-step self-etching adhesive systems performing best and 1-step self-etching adhesive systems performing worst; 3-step etch-and-rinse systems, glass ionomers/resin-modified glass ionomers, 2-step etch-and-rinse systems and polyacid-modified resin composites were ranked in between. Restorations placed in teeth whose dentin/enamel had been prepared/roughened showed a statistically significant higher retention rate than those placed in teeth with unprepared dentin (p < 0.05). Beveling of the enamel and the type of isolation used (rubberdam/cotton rolls) had no significant influence. Significance: The clinical performance of cervical restorations is significantly influenced by the type of adhesive system used and/or the adhesive class to which the system belonged and whether the dentin/enamel is prepared or not. 2-Step self-etching- and 3-step etch&rinse systems shall be chosen over 1-step self-etching systems and glass ionomer derivates. The dentin (and enamel) surface shall be roughened before placement of the restoration. © 2010 Academy of Dental Materials.

Von Pawel J.,Asklepios Fachkliniken Munich Gauting | Harvey J.H.,Alabama Oncology | Spigel D.R.,Sarah Cannon Research Institute | Dediu M.,Institute Of Oncology Prof Dr Alexandru Trestioreanu | And 5 more authors.
Clinical Lung Cancer | Year: 2014

Background This phase II study examined the efficacy of mapatumumab in combination with paclitaxel and carboplatin in patients with non-small-cell lung cancer (NSCLC). Patients and Methods Patients with stage IIIB or stage IV advanced primary NSCLC were randomly assigned (1:1:1) to receive up to 6 courses of standard-dose paclitaxel and carboplatin or a combination of paclitaxel, carboplatin, and mapatumumab (10 mg/kg or 30 mg/kg). Primary efficacy end points were overall response rate and median progression-free survival (PFS). Secondary efficacy end points included disease control rate, overall survival (OS), time to response, and duration of response. Exploratory studies included evaluation of historical biopsy materials for TRAIL-R1 expression by immunohistochemical analysis and serum levels of M30, a marker of apoptosis, before and after the first 2 doses of mapatumumab. Safety parameters, including adverse events (AEs), laboratory tests, and immunogenicity, were assessed. Results The majority of patients had stage IV disease (79%) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (58%); baseline characteristics were similar across treatment arms. No improvements in response or disease control rates, PFS, or OS were gained from the addition of mapatumumab. Adverse events in the mapatumumab arms were generally consistent with toxicities seen in the carboplatin and paclitaxel control arm. Levels of M30 were highly variable, and consistent patterns were not seen across treatment arms. Conclusion This study showed no clinical benefit from adding mapatumumab to carboplatin and paclitaxel in unselected patients with NSCLC. The combination was generally well tolerated. The possibility of subgroups sensitive to mapatumumab is discussed. © 2014 Elsevier Inc. All rights reserved.

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