Discovery of new cinnamic acid amides as novel antifibrotic drugs

Fibrosis is a common hallmark of most fatal chronic diseases in the industrialized world. Among pulmonary disease, progressive fibrosis is the pivotal pathomechanism of the Idiopathic Pulmonary Fibrosis (IPF), a devastating progressive interstitial lung disease with a median patient survival time of 3-5 years. Approved pharmacotherapies only slow down, but do not stop disease progression. Thus, new antifibrotic therapeutic strategies are urgently needed. Like most fibrotic diseases, IPF pathogenesis is characterized by the deposition of excessive amounts of fibrotic extracellular matrix of activated myofibroblasts resulting in increasing loss of lung function. A phenotypic high-content ECM deposition assay was developed measuring fibrotic ECM deposition by primary human lung fibroblasts (phLFs) derived from IPF patients upon transforming growth factor beta 1 (TGFβ1) and drug treatment. To identify antifibrotic compounds, 1509 small molecule compounds were screened for inhibition of TGFβ1-induced ECM deposition. Using a deep learning model 31 hit compounds were identified. Here, for the compound Tranilast a low-potent inhibitory activity on TGFβ1-induced fibroblast-myofibroblast-transdifferentiation and ECM deposition was found. By structure-activity-relationship studies of Tranilast derivatives, a group of novel cinnamic acid amides, in particular N-(2-butoxyphenyl)-3-(phenyl)acrylamides and N-(2-benzoxyphenyl)-3-(phenyl)acrylamides (N23Ps), with high potency for the inhibition of TGFβ1-dependent αSMA induction and ECM deposition was discovered. N23Ps induced strong morphological changes in phLFs, possibly due to a regulation of cytoskeletal proteins as seen in transcriptome-wide microarray analysis. Furthermore, proteomics and transcriptomics analysis showed N23Ps to inhibit specific fibrotic signatures in TGFβ1-treated phLFs as well as in a human ex-vivo injury and early 3D fibrosis model based on human precision cut lung slice tissue cultures. RNA interference rescue experiments showed an inhibition of TGFβ1 signaling by N23Ps to be SMURF2-dependent. In conclusion, a novel group of cinnamic acid amides was discovered that inhibit TGFβ1-induced profibrotic behavior of myofibroblasts in a SMURF2-dependent way.Fibrotische Gewebeveränderungen stellen ein gemeinsames Merkmal der häufigsten letalen Erkrankungen in der industrialisierten Welt dar. Unter den Lungenerkrankungen ist hier allen voran die Idiopathische Lungenfibrose (IPF) durch einen fortschreitende fibrotischen Umbau des Lungenparenchyms charakterisiert. Zugelassene antifibrotische Pharmakotherapien verlangsamen das Progress der Erkrankung, können diesen jedoch nicht aufhalten. IPF-Patienten überleben im Median 3-5 Jahre nach Diagnosestellung. Hieraus ergibt sich ein dringender Bedarf an neuen antifibrotischen Wirkstoffen und Therapien. Wie in anderen fibrotischen Erkrankungen, ist die Pathogenese der IPF durch die pulmonale Deposition erhöhter Mengen von extrazellulärer Matrix (EZM), größtenteils durch aktivierte Myofibroblasten charakterisiert. Es wurde ein phänotypisches immunocytochemisches, sogenanntes high-content, Hochdurchsatz-Assay zur Messung von fibrotischer EZM-Deposition durch mit transforming growth factor β 1 (TGFβ1) und Wirkstoffen behandelten primäre humane Lungenfibroblasten (phLFs) entwickelt, welche aus Lungengewebe von IPF-Patienten isoliert wurden. 1509 niedermolekulare Wirkstoffe wurden auf eine Inhibition TGFβ1-stimulierter Extrazellulärmatrix-Deposition durch phLFs gescreent. Mithilfe einer Deeplearning-basierten Immunofluoreszenzanalyse des Assays konnten 31 antifibrotische Wirkstoffkandidaten identifiziert werden. Der Wirkstoff Tranilast wies eine niederpotente Inhibition von TGFβ1-induzierter Fibroblasten-Myofibroblasten-Transdifferenzierung sowie TGFβ1-induzierter Extrazellulärmatrix-Deposition auf. Durch die Untersuchung der Struktur-Wirkungsbeziehung von Tranilast-Derivaten, konnte eine neue Gruppe hochpotenter Inhibitoren von TGFβ1-induzierter Fibroblasten-Myofibroblasten-Transdifferenzierung sowie TGFβ1-induzierter Extrazellulärmatrix-Deposition, bestehend aus den Zimtsäureamiden der N-(2-butoxyphenyl)-3-(phenyl)acrylamid- and N-(2-benzoxyphenyl)-3-(phenyl)acrylamid-Gruppe (N23Ps), entdeckt werden. Im Folgenden konnte gezeigt werden, dass N23Ps eine starke Morphologie-Änderung in den pHLFs induzieren, wahrscheinlich aufgrund einer Regulation zytoskeletaler Proteine. Anschließende Transkriptom- und Proteomanalysen zeigten, dass N23Ps spezifische fibrotische Signaturen in TGFβ1-behandelten pHLFs sowie in einem humanen ex-vivo Model für frühe lungenfibrotischen Veränderungen, basierend auf Gewebekulturen von humanen precision cut lung slices (hPCLS), inhibieren. RNA-Interferenz-Experimente zeigten, dass die Inhibition von TGFβ1-Signalwegen durch N23Ps von der Ubiquitin-Protein-Ligase SMURF2 abhängig ist. Zusammenfassend wurde eine neue Gruppe an Zimtsäureamiden entdeckt, welche TGFβ1-induzierte profibrotische Myofibroblastenaktivität SMURF2-abhängig hemmt

Intravascular ultrasound-guided stenting of left main stem dissection after medtronic corevalve implantation

Transcatheter aortic valve implantation (TAVI) implies the introduction, positioning, and deployment of a stented bioprosthesis in the (calcified) native aortic valve. We report an at first glance uneventful TAVI with the Medtronic Corevalve System, which was followed by transient electrocardiographic changes suggesting acute left main stem disease. The diagnosis of acute left main stem dissection extending from the left coronary cusp was firmly established by intravascular ultrasound. The ostium of the left main stem was successfully treated with intravascular ultrasound-guided placement of a drug eluting stent

Design of Automobile Testing Plant Including Absorption Dynamometer

No abstract

Cost-utility of transcatheter aortic valve implantation for inoperable patients with severe aortic stenosis treated by medical management: a UK cost-utility analysis based on patient-level data from the ADVANCE study.

OBJECTIVE: To use patient-level data from the ADVANCE study to evaluate the cost-effectiveness of transcatheter aortic valve implantation (TAVI) compared to medical management (MM) in patients with severe aortic stenosis from the perspective of the UK NHS. METHODS: A published decision-analytic model was adapted to include information on TAVI from the ADVANCE study. Patient-level data informed the choice as well as the form of mathematical functions that were used to model all-cause mortality, health-related quality of life and hospitalisations. TAVI-related resource use protocols were based on the ADVANCE study. MM was modelled on publicly available information from the PARTNER-B study. The outcome measures were incremental cost-effectiveness ratios (ICERs) estimated at a range of time horizons with benefits expressed as quality-adjusted life-years (QALY). Extensive sensitivity/subgroup analyses were undertaken to explore the impact of uncertainty in key clinical areas. RESULTS: Using a 5-year time horizon, the ICER for the comparison of all ADVANCE to all PARTNER-B patients was £13 943 per QALY gained. For the subset of ADVANCE patients classified as high risk (Logistic EuroSCORE >20%) the ICER was £17 718 per QALY gained). The ICER was below £30 000 per QALY gained in all sensitivity analyses relating to choice of MM data source and alternative modelling approaches for key parameters. When the time horizon was extended to 10 years, all ICERs generated in all analyses were below £20 000 per QALY gained. CONCLUSION: TAVI is highly likely to be a cost-effective treatment for patients with severe aortic stenosis

Predictors of mortality following corevalve transcatheter aortic valve implantation: results from the ADVANCE study

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Impact of Anesthesia Type on Outcomes of Transcatheter Aortic Valve Implantation (from the Multicenter ADVANCE Study).

Transcatheter aortic valve implantation (TAVI) has become the standard of care for many patients with symptomatic severe aortic stenosis who are at increased risk of morbidity and mortality during surgical aortic valve replacement. However, there is still no general consensus regarding the use of general anesthesia (GA) versus local anesthesia with sedation (non-GA) during the TAVI procedure. Using propensity score-matching analysis, we analyzed the characteristics and outcomes of patients who underwent TAVI with either GA (n = 245) or non-GA (n = 245) in the fully monitored, international, CoreValve ADVANCE Study. No statistically significant differences existed between the non-GA and GA groups in all-cause mortality (25.4% vs 23.9%, p = 0.78), cardiovascular mortality (16.4% vs 16.6%, p = 0.92), or stroke (5.2% vs 6.9%, p = 0.57) through 2-year follow-up. Major vascular complications were more common in the non-GA group. Total hospital stay was similar between the 2 groups. Conversion from non-GA to GA occurred in 13 patients (5.3%) because of procedural complications in 9 patients and discomfort or restlessness in 4 patients. Most procedural complications were related to valve positioning or vascular issues. Two of the 13 converted patients died during the procedure. Both GA and non-GA are widely used in real-world TAVI practice, and the decision appears to be guided by only a few patient-related factors and dominated by local and national practice. The outcomes of both anesthesia modes are equally good. When conversion from non-GA did occur, the complication requiring GA affected outcomes

Transcatheter aortic valve implantation: predictors of procedural success—the Siegburg-Bern experience

Aims The purpose of the present analysis was to identify predictors of procedural success of percutaneous transcatheter aortic valve implantation (TAVI). Methods and results We prospectively assessed in-hospital outcome of patients undergoing TAVI at two institutions. We analysed clinical, morphological, and procedural parameters using univariate and multivariate regression models. Between 2005 and 2008, a total of 168 consecutive patients with symptomatic aortic valve stenosis underwent TAVI using the self-expanding CoreValve Revalving prosthesis. Patients (93%) were highly symptomatic with a New York Heart Association grade III/IV and a mean aortic valve area of 0.66 ± 0.21 cm2. Acute and in-hospital procedural success rates were 90.5 and 83.9%, respectively, with an in-hospital mortality, myocardial infarction, and stroke rate of 11.9, 1.8, and 3.6%, respectively. Predictors of in-hospital procedural success were type of access (OR 0.33, 95% CI 0.13-0.82, P = 0.017), prior coronary intervention (OR 5.3, 95% CI 1.20-23.41, P = 0.028) and pre-procedural Karnofsky index using univariate regression. Pre-procedural Karnofsky index emerged as the only independent predictor (OR 1.04, 95% CI 1.00-1.08, P = 0.032) in the multivariate analysis. Conclusion Pre-procedural functional performance status predicts the in-hospital outcome after TAVI. Patients with a good functional status are likely to benefit more from TAVI than previously reported high-risk patient

Transcatheter aortic valve implantation: predictors of procedural success--the Siegburg-Bern experience

The purpose of the present analysis was to identify predictors of procedural success of percutaneous transcatheter aortic valve implantation (TAVI)