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Heintze S.D.,Preclinical Research | Eser A.,Preclinical Research | Monreal D.,Preclinical Research | Rousson V.,University of Lausanne
Journal of the Mechanical Behavior of Biomedical Materials | Year: 2017

Objective Dynamic loading is a more important predictor for the clinical longevity of ceramic crowns than static loading. However, dynamic loading machines are costly and mostly have only one test station. The SD Mechatronik Chewing Simulator (formerly Willytec) may be a cost-effective alternative to evaluate the fatigue resistance of metal ceramic crowns. Method Four metal ceramic materials were tested on lower first molar crowns: GC InitiaI, Creation (Willy Geller), IPS InLine (Ivoclar Vivadent) and the new low-fusion IPS Style Ceram (Ivoclar Vivadent). The ceramic material was manually layered on frames made of the nickel-chromium alloy 4all (Ivoclar Vivadent) by using a silicone mould. The crowns were adhesively luted to PMMA dies. Dynamic loading was carried out with a SD Mechatronik Chewing Simulator using additional bars with weights. A steel antagonist (Ø 4 mm) with 40 mm/s downward speed hit the disto-buccal cusp of the crown with minimal impulse while sliding for a distance of 0.7 mm. The starting load was 250 N. The forces at each load level had been verified with a 3D force sensor (Kistler). Four crowns per group and load were submitted to four decreasing load levels for 200,000 cycles with a resulting simulation frequency of 0.9 Hz and simultaneous thermocycling (5 °C/55 °C) until all four crowns no longer showed chippings. Statistical analyses had been carried out using an exponential, a Weibull and a lognormal model. The fatigue resistance was defined as the maximal load for which one would observe less than 1% failure after 200,000 cycles. In addition to the fatigue testing of the molar crowns, simulations of finite element method (FEM) were conducted in order to investigate the influence of the mismatch of the thermal expansion coefficient (CTE) between the PMMA die and the molar crown on the fatigue resistance. Results The 3D-force measurements revealed that the summarised forces were very similar to the force of the dead weights that were put on the bars. The failure modes consisted of cracks and small and big chippings. Chi-square test and Gamma revealed no statistically significant differences between the four test materials in relation to the failure mode. At 250 N all materials showed chippings within the ceramic or down to the metal frame, while at lower loads there were differences. The estimated fatigue resistance was 68 N for GC Initial, 88 N for Creation, 96N for IPS Style Ceram, and 105 N for IPS InLine, when using a Weibull model and considering all possible events. Furthermore, FEM simulations revealed that the maximum values of the maximum principal stress were 90 MPa for the thermocycling and 225 MPa for the external load. Conclusion The SD Mechatronik Chewing Simulator is an adequate and cost-effective tool to test layered PFM crowns for fatigue resistance. The test method and the chewing simulator can be used for ceramic on metal, ceramic on zirconia and monolithic ceramic materials. © 2016 Elsevier Ltd


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.


Yu Y.,ArQule | Savage R.E.,ArQule | Eathiraj S.,ArQule | Meade J.,Preclinical Research | And 4 more authors.
PLoS ONE | Year: 2015

As a critical component in the PI3K/AKT/mTOR pathway, AKT has become an attractive target for therapeutic intervention. ARQ 092 and a next generation AKT inhibitor, ARQ 751 are selective, allosteric, pan-AKT and AKT1-E17K mutant inhibitors that potently inhibit phosphorylation of AKT. Biochemical and cellular analysis showed that ARQ 092 and ARQ 751 inhibited AKT activation not only by dephosphorylating themembrane-associated active form, but also by preventing the inactive form from localizing into plasma membrane. In endometrial PDX models harboring mutant AKT1-E17K and other tumormodels with an activated AKT pathway, both compounds exhibited strong anti-tumor activity. Combination studies conducted in in vivo breast tumor models demonstrated that ARQ 092 enhanced tumor inhibition of a common chemotherapeutic agent (paclitaxel). In a large panel of diverse cancer cell lines, ARQ 092 and ARQ 751 inhibited proliferation across multiple tumor types but were most potent in leukemia, breast, endometrial, and colorectal cancer cell lines.Moreover, inhibition by ARQ 092 and ARQ 751 was more prevalent in cancer cell lines containing PIK3CA/ PIK3R1 mutations compared to those with wt-PIK3CA/PIK3R1 or PTEN mutations. For both ARQ 092 and ARQ 751, PIK3CA/PIK3R1 and AKT1-E17Kmutations can potentially be used as predictive biomarkers for patient selection in clinical studies. Copyright © 2015 Yu et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.


Heintze S.D.,Preclinical Research | Monreal D.,Preclinical Research | Rousson V.,University of Lausanne
Journal of the Mechanical Behavior of Biomedical Materials | Year: 2016

Aims: There is no standard test to determine the fatigue resistance of denture teeth. With the increasing number of patients with implant-retained dentures the mechanical strength of the denture teeth requires more attention and valid laboratory test set-ups. The purpose of the present study was to determine the fatigue resistance of various denture teeth using a dynamic load testing machine. Methods: Four denture teeth were used: Bonartic II (Candulor), Physiodens (Vita), SR Phonares II (Ivoclar Vivadent) and Trubyte (Dentsply). For dynamic load testing, first upper molars with a similar shape and cusp inclination were selected. The molar teeth were embedded in cylindrical steel molds with denture base material (ProBase, Ivoclar Vivadent). Dynamic fatigue loading was carried out on the mesio-buccal cusp at a 45° angle using dynamic testing machines and 2,000,000 cycles at 2. Hz in water (37. °C). Three specimens per group and load were submitted to decreasing load levels (at least 4) until all the three specimens no longer showed any failures. All the specimens were evaluated under a stereo microscope (20× magnification). The number of cycles reached before observing a failure, and its dependence on the load and on the material, has been modeled using a parametric survival regression model with a lognormal distribution. This allowed to estimate the fatigue resistance for a given material as the maximal load for which one would observe less than 1% failure after 2,000,000 cycles. Results: The failure pattern was similar for all denture teeth, showing a large chipping of the loaded mesio-buccal cusp. In our regression model, there were statistically significant differences among the different materials, with SR Phonares II and Bonartic II showing a higher resistance than Physiodens and Trubyte, the fatigue resistance being estimated at around 110. N for the former two, and at about 60. N for the latter two materials. Conclusion: The fatigue resistance may be a useful parameter to assess and to compare the clinical risk of chipping and fracture of denture tooth materials. © 2015 Elsevier Ltd.


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 | Albrecht T.,Preclinical Research | Cavalleri A.,Preclinical Research | Steiner M.,University of Kiel
Dental Materials | Year: 2011

Objectives: The purpose of this study was to validate a new laboratory method to test all-ceramic systems with regard to the proportion of failures. Methods: Sixteen standardized mandibular molar crowns consisting of two different materials (IPS Empress, IPS e.max Press) were adhesively luted on CAD/CAM milled PMMA abutments (first lower molar, circular chamfer). All crowns were loaded applying an eccentric force in a Willytec chewing simulator (steel stylus, Ø 2.4 mm, 2 mm lateral movement from fossa to cuspal tip) with stepwise increase of the load (3, 5, 9 kg, 100,000 cycles each, 0.8 Hz) and simultaneous thermocycling (5 °C/55 °C × 417 per phase). Another four crowns of each material were subjected to force measurements with a 3D force sensor during dynamic loading of each loading phase using two different lateral movements (from fossa to cusp and vice versa). Results: The cumulative forces for the three directions in space were much higher compared to the static load of the chewing simulator (maximal force at 3 kg 60 N, 5 kg 160 N, 9 kg 240 N). There was no statistically significant difference in the mean or maximal force between the two materials or two different lateral movements. During dynamic loading, no fractures occurred in the molar crowns made of IPS e.max Press, whereas 50% of the IPS Empress crowns showed failures (75% fractures and 25% chippings) (log-rank test p = 0.002). Most of the Empress crowns fractured during the third loading phase (9 kg). Conclusions: The forces that the dead weights exerted during dynamic loading were 2-3 times higher than those during static loading. None of the lithium disilicate ceramic molar crowns fractured, whereas half of the leucite reinforced molar crowns failed during dynamic loading. © 2010 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.


PubMed | Ludwig Maximilians University of Munich, University of Lausanne, State University of Ponta Grossa and Preclinical Research
Type: | Journal: Dental materials : official publication of the Academy of Dental Materials | Year: 2016

To evaluate a range of mechanical parameters of composite resins and compare the data to the frequency of fractures and wear in clinical studies.Based on a search of PubMed and SCOPUS, clinical studies on posterior composite restorations were investigated with regard to bias by two independent reviewers using Cochrane Collaborations tool for assessing risk of bias in randomized trials. The target variables were chipping and/or fracture, loss of anatomical form (wear) and a combination of both (summary clinical index). These outcomes were modelled by time and material in a linear mixed effect model including random study and experiment effects. The laboratory data from one test institute were used: flexural strength, flexural modulus, compressive strength, and fracture toughness (all after 24-h storage in distilled water). For some materials flexural strength data after aging in water/saliva/ethanol were available. Besides calculating correlations between clinical and laboratory outcomes, we explored whether a model including a laboratory predictor dichotomized at a cut-off value better predicted a clinical outcome than a linear model.A total of 74 clinical experiments from 45 studies were included involving 31 materials for which laboratory data were also available. A weak positive correlation between fracture toughness and clinical fractures was found (Spearman rho=0.34, p=0.11) in addition to a moderate and statistically significant correlation between flexural strength and clinical wear (Spearman rho=0.46, p=0.01). When excluding those studies with high risk of bias (n=18), the correlations were generally weaker with no statistically significant correlation. For aging in ethanol, a very strong correlation was found between flexural strength decrease and clinical index, but this finding was based on only 7 materials (Spearman rho=0.96, p=0.0001). Prediction was not consistently improved with cutoff values.Correlations between clinical and laboratory outcomes were moderately positive with few significant results, fracture toughness being correlated with clinical fractures and flexural strength with clinical wear. Whether artificial aging enhances the prognostic value needs further investigations.


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.

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