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As one of the first Direct Acting Antivirals (DAA), the protease inhibitor Telaprevir (TVR) was available in the European Union from 9/2011 until 9/2016 as a new treatment option for chronic Hepatitis C.Aim. To assess the implementation of therapy stopping rules or shortening of the treatment and their impact on sustained virological response (SVR), as well as the safety and efficacy of the TVR-based therapy during routine daily treatment of patients in Germany.Materials and Methods. 802 patients were assessed (272 treatment naïve, 520 pre-treated) in the noninterventional, multi-center study.Results. 56.6 % of the patients achieved SVR. SVR rate was higher in patients with relapse after previous treatment (68.0 %) than in patients with a previous null-response (31.1 %) and in previously untreated patients (58.1 %). Stopping rule conditions were fulfilled by 3.2 % of patients and it was implemented in 65.4 % of these. 34.3 % of the patients fulfilled the conditions for a therapy shortening. This rule was adhered to in 48.4 % of these, in 34.5 % it was not adhered to. Thus recommendations were not always being followed. Therapy shortening was considered more frequently in previously untreated (54.8 %) than for previously treated patients (24.2 %). Stopping rule application but not shortened treatment reduced therapy costs.Conclusion. The TVR-based therapy represented a breakthrough at that time. Further DAAs have been added as therapeutic options since, increasing the complexity of treatment choice and correct implementation. They represent both an opportunity and a challenge for all those involved.As one of the first Direct Acting Antivirals (DAA), the protease inhibitor Telaprevir (TVR) was available in the European Union from 9/2011 until 9/2016 as a new treatment option for chronic Hepatitis C.Aim. To assess the implementation of therapy stopping rules or shortening of the treatment and their impact on sustained virological response (SVR), as well as the safety and efficacy of the TVR-based therapy during routine daily treatment of patients in Germany.Materials and Methods. 802 patients were assessed (272 treatment naïve, 520 pre-treated) in the noninterventional, multi-center study.Results. 56.6 % of the patients achieved SVR. SVR rate was higher in patients with relapse after previous treatment (68.0 %) than in patients with a previous null-response (31.1 %) and in previously untreated patients (58.1 %). Stopping rule conditions were fulfilled by 3.2 % of patients and it was implemented in 65.4 % of these. 34.3 % of the patients fulfilled the conditions for a therapy shortening. This rule was adhered to in 48.4 % of these, in 34.5 % it was not adhered to. Thus recommendations were not always being followed. Therapy shortening was considered more frequently in previously untreated (54.8 %) than for previously treated patients (24.2 %). Stopping rule application but not shortened treatment reduced therapy costs.Conclusion. The TVR-based therapy represented a breakthrough at that time. Further DAAs have been added as therapeutic options since, increasing the complexity of treatment choice and correct implementation. They represent both an opportunity and a challenge for all those involved. Ингибитор протеазы Телапревир (ТПВ) является одним из первых противовирусных препаратов прямого действия (ПППД) и применялся в странах Евросоюза при лечении хронического гепатита С в качестве нового метода с сентября 2011 года по сентябрь 2016 года. Цель: Оценить применение правил остановки (прекращения) или сокращения периода терапии и их влияние на устойчивый вирусологический ответ (УВО), а также безопасность и эффективность противовирусной терапии на основе ТПВ при рутинном применении в Германии. Материалы и методы. В неинтервенционном мультицентровом исследовании участвовали 802 пациента (272 пациента, ранее не получавшие, и 520 пациентов, ранее получавшие противовирусные препараты). Результаты. Устойчивый вирусологический ответ (УВО) был достигнут у 56,6 % пациентов. Доля пациентов с УВО среди пациентов с рецидивом после предыдущего лечения была выше (68,0 %), чем у пациентов с предыдущим нулевым ответом (31,1 %) и у пациентов, ранее не получавших противовирусные препараты (58,1 %). Критериям прекращения терапии соответствовали 3,2 % пациентов, из них у 65,4 % лечение было остановлено. Критериям сокращения терапии соответствовали 34,3 % пациентов. Это правило было применено в отношении 48,4 % из них, у 34,5 % оно не соблюдалось. Таким образом, не всегда соблюдались рекомендации по прекращению или сокращению терапии. Чаще терапию сокращали в группе пациентов, ранее не получавших лечения (54,8%), чем в группе пациентов, получавших противовирусную терапию в анамнезе (24,2%). Именно применение правил прекращения терапии, а не сокращение ее продолжительности, позволило снизить затраты на лечение. Заключение. Терапия на основе ТПВ в свое время стала прорывом в лечении гепатита С. Позже были предложены новые варианты ПППД для терапии, что усложнило выбор и точность применения препаратов. ПППД привнесли одновременно как новые возможности, так и новые сложности.

Suprachiasmatic nuclei (SCN) neurons contain an intracellular molecular circadian clock and the Cryptochromes (CRY1/2), key transcriptional repressors of this molecular apparatus, are subject to post-translational modification through ubiquitination and targeting for proteosomal degradation by the ubiquitin E3 ligase complex. Loss-of-function point mutations in a component of this ligase complex, Fbxl3, delay CRY1/2 degradation, reduce circadian rhythm strength, and lengthen the circadian period by ∼2.5 h. The molecular clock drives circadian changes in the membrane properties of SCN neurons, but it is unclear how alterations in CRY1/2 stability affect SCN neurophysiology. Here we use male and female Afterhours mice which carry the circadian period lengthening loss-of-function Fbxl3Afh mutation and perform patch-clamp recordings from SCN brain slices across the projected day/night cycle. We find that the daily rhythm in membrane excitability in the ventral SCN (vSCN) was enhanced in amplitude and delayed in timing in Fbxl3Afh/Afh mice. At night, vSCN cells from Fbxl3Afh/Afh mice were more hyperpolarized, receiving more GABAergic input than their Fbxl3+/+ counterparts. Unexpectedly, the progression to daytime hyperexcited states was slowed by Afh mutation, whereas the decline to hypoexcited states was accelerated. In long-term bioluminescence recordings, GABAA receptor blockade desynchronized the Fbxl3+/+ but not the Fbxl3Afh/Afh vSCN neuronal network. Further, a neurochemical mimic of the light input pathway evoked larger shifts in molecular clock rhythms in Fbxl3Afh/Afh compared with Fbxl3+/+ SCN slices. These results reveal unanticipated consequences of delaying CRY degradation, indicating that the Afh mutation prolongs nighttime hyperpolarized states of vSCN cells through increased GABAergic synaptic transmission. SIGNIFICANCE STATEMENT The intracellular molecular clock drives changes in SCN neuronal excitability, but it is unclear how mutations affecting post-translational modification of molecular clock proteins influence the temporal expression of SCN neuronal state or intercellular communication within the SCN network. Here we show for the first time, that a mutation that prolongs the stability of key components of the intracellular clock, the cryptochrome proteins, unexpectedly increases in the expression of hypoexcited neuronal state in the ventral SCN at night and enhances hyperpolarization of ventral SCN neurons at this time. This is accompanied by increased GABAergic signaling and by enhanced responsiveness to a neurochemical mimic of the light input pathway to the SCN. Therefore, post-translational modification shapes SCN neuronal state and network properties.

Hintergrund: Plaque Psoriasis geht einher mit übermäßig starker Schuppung, Juckreiz und Schmerzen. Als Erfolgsparameter einer Biologika-Therapie spielt neben der Verbesserung des Hautbildes die Patientenbeurteilung des Therapieerfolgs (patient reportet outcome, PRO) eine wesentliche Rolle.[zum vollständigen Text gelangen Sie über die oben angegebene URL], 26. Fortbildungswoche für praktische Dermatologie und Venerologie

Menthol bewirkt eine Kälteempfindung wenn es mit der Haut oder Schleimhaut in Berührung kommt. Der zugrunde liegende molekulare Mechanismus ist jedoch noch nicht vollständig geklärt. Die Inhibition von Ca2+-Kanälen mit der Folge einer Reduktion von Ca2+ abhängigen K+-Strömen wurde diskutiert. Außerdem zeigen Messungen an DRG-Neuronen eine Aktivierung des TRPM8-(CMR1)Kanals durch Menthol sowie eine damit einhergehende Depolarisation der Zellmembran durch Ca2+-Einstrom. Darüber hinaus zeigen kürzlich publizierte Studien verschiedene Interaktionen von Menthol, wie die Exzitation von TRPV3- und die Inhibition von TRPA1- (ANKTM1) Kanälen. In der hier vorliegenden Arbeit wurde Menthol verwendet, um die Desensibilisierung auf die hypothalamische Zelllinie GT1-7 zu untersuchen. PCR, Ca2+-Imaging und die Patch- Clamp Technik wurden dazu eingesetzt. In PCR Experimenten konnte die Expression von TRPM8-mRNA nachgewiesen werden, jedoch zeigte das Ca2+-Imaging keinen Anstieg von intrazellulärem Ca2+ während der Mentholapplikation. Die Patch-Clamp-Experimente zeigten eine starke Reduktion von Auswärtsströmen, die mit den bisherigen Annahmen über die Mentholwirkung über TRP-Kanäle nicht hinreichend erklärt werden können. Die Daten zeigen eine dosisabhängige Inhibition von spannungsabhängigen K+-Kanälen. Messungen mit einer K+-Konzentration von 140 mM in der Badlösung unterstützen dieses Konzept. Der Effekt auf K+-Kanäle blieb auch in Ca2+ freier Badlösung weitgehend erhalten. Um zu untersuchen, ob neben K+-Kanälen weitere Kanäle geblockt werden, wurden Na+-Ströme isoliert. Hierbei zeigte sich kein Effekt von Menthol auf Na+-Kanäle. Die zwei Hauptkomponenten des spannungsabhängigen K+-Stroms (delayed rectifier vom A- und DR-Typ) wurden aufgrund ihrer unterschiedlichen Aktivierungscharakteristiken unterschieden. Menthol blockt hauptsächlich die DR-Ströme, während die A-Ströme unberührt bleiben. In einer Dosis-Wirkungs-Kurve betrug der EC50-Wert aller geblockten Auswärtsströme 380 μM. Durch den Block des DR-Stroms kann sich die Form des Aktionspotentials verändern. Funktionell kann dies zu einem veränderten Feuermuster von einzelnen Neuronen und somit zu einer veränderten Hormonfreisetzung führen., It is well known that menthol evokes a sensation of cold when applied to skin or mucosa. The underlying ionic mechanisms, however, are still under debate. Blockade of Ca2+ currents with reduction of Ca2+ dependent K+ currents have been discussed. Recordings from DRG neurons clearly demonstrated menthol induced activation of TRPM8 (CMR1) ion channels and depolarisation of the cell membrane caused by Ca2+ influx. Moreover, recent studies suggest multiple actions of menthol including, for example, excitation of TRPV3 and inhibition of TRPA1 (ANKTM1) channels. Here menthol was used as an agent to examine desensitization effects on a hypothalamic GT1-7 neuronal cell line by using PCR, Ca2+-Imaging and whole cell patch clamp techniques. PCR studies verified the expression of TRPM8 mRNA, but Ca2+-Imaging does not show an increase of intracellular Ca2+ during menthol application. The patch-clamp studies demonstrated a pronounced reduction of an outward current which cannot be explained by the conventional assumptions about the action of menthol via TRP channels. The data point to a dose dependent inhibition of voltage-dependent K+ channels which is completely reversible. Recordings made under extracellular K+ concentration of 140 mM support this concept. Menthol effects occurred also in Ca2+ free bath solution. To examine whether menthol affects further currents besides K+, Na+ currents were isolated and are not affected by menthol. The two major voltage dependent K+-currents (delayed rectifier of A- and DR-current) were identified according to their different activation characteristics. Menthol blocks the majority of DR-currents, while the A-currents persist. In a dose response curve the EC50 value of all blocked outward-currents is 380 μM. As menthol blocks the DR-type K+ current, the shape of APs might be changed. Functionally, this could lead to different firing rates and patterns, which is thought to influence hormone release.