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Externer brief

Riociguat
Riociguat is an investigational, oral treatment that was discovered and developed by Bayer to target a key molecular mechanism underlying pulmonary hypertension (PH). Riociguat is being investigated as a new and specific approach to treat different types of PH.1, 2 PH is a severe, progressive, life-changing and life-threatening disorder of the heart and lungs in which the blood pressure in the pulmonary arteries is above normal and which can lead to heart failure There are five types of PH; each can affect the patient in a different way and every patient may have a different etiology and manifestation of PH.5-7 Riociguat is the first and only drug that has consistently demonstrated robust clinical efficacy in two separate PH indications: chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension The novel science of riociguat
Riociguat is a soluble guanylate cyclase (sGC) stimulator, the first member of a novel class of compounds.1, 2 sGC is an enzyme found in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme enhances synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP). cGMP plays an important role in regulating vascular tone, proliferation, fibrosis, and inflammation.10 PH is associated with endothelial dysfunction, impaired synthesis of NO and insufficient stimulation of sGC.1 Riociguat has a unique mode of action: it sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. Riociguat also directly stimulates sGC via a different binding site, independently of NO.1, 2, 10 Riociguat, as a stimulator of sGC, addresses the issue of NO deficiency by restoring the NO-sGC-cGMP pathway, leading to increased generation of Riociguat aims to address areas of high unmet medical need
Although the prognosis for patients with PH has improved in recent years, there is still a high unmet need for more efficient therapies.11 With its novel mode of action, riociguat has the potential to overcome a number of limitations of currently approved PAH therapies, including NO dependence, and is the first drug which has shown clinical benefits in CTEPH, where no pharmacological treatment is approved.* 1, 8 Positive results for riociguat in PH
Chronic thromboembolic pulmonary hypertension (CTEPH) and riociguat
CHEST (Chronic Thromboembolic Pulmonary Hypertension sGC-Stimulator Trial) is a Phase
III program which assessed the efficacy and safety of oral riociguat in the treatment of patients with either inoperable CTEPH or PH which persisted or reoccurred after pulmonary endarterectomy (PEA). CHEST is a multi-center, multi-national program with active centers in 26 countries. The program includes a randomized, double-blinded, placebo-controlled pivotal trial phase (CHEST-1) and an open label long-term extension trial phase (CHEST-2). In the CHEST-1 study, 261 patients with inoperable CTEPH or with persistent or recurrent pulmonary hypertension after PEA were randomized and treated with either riociguat or placebo orally for 16 weeks. Riociguat was titrated, over a period of eight weeks in doses of 0.5 mg increments, from 1.0 mg up to 2.5 mg, three times a day. After the titration phase, patients were followed up for another eight weeks on their last dose to complete CHEST-1. Patients from both arms then had the option of participating in the open label long term extension study (CHEST-2), starting with an eight-week double-blinded sham titration. The ongoing CHEST-2 study is investigating the sustainability of the efficacy results, as well as longer term safety aspects of riociguat for CTEPH patients. CHEST-1 results
CHEST-1 met its primary endpoint, with riociguat shown to be the first ever drug to significantly improve exercise capacity in patients with CTEPH. In the study, riociguat demonstrated a statistically significant improvement in the six-minute walk test (6MWT) from baseline after 16 weeks compared with placebo.8 A statistically significant improvement in exercise capacity with riociguat was observed as early as four weeks after treatment initiation and improved further in the long term extension study, CHEST-2, whilst the safety profile was Riociguat also showed statistically significant improvements in relevant secondary endpoints, including pulmonary vascular resistance (PVR), N-terminal prohormone brain natriuretic peptide (NT-proBNP) and WHO functional class (FC).12 The improvements in 6MWD and * Please note that riociguat has already been approved and launched under the brand name Adempas® in some countries for the treatment of PAH and/or CTEPH. WHO FC observed during the pivotal 16-week CHEST-1 study were sustained during long- term extension in the CHEST-2 study for a further 12 weeks and data suggests sustained improvements over one year of observation.13 Pulmonary arterial hypertension (PAH) and riociguat
PATENT (Pulmonary Arterial Hypertension sGC-Stimulator Trial) is a Phase III program to
assess the efficacy and safety of oral riociguat in the treatment of treatment naïve and pre- treated patients with symptomatic PAH. PATENT is a multi-center, multi-national program with active centers in 30 countries. The program includes a randomized, double-blinded, placebo- controlled pivotal trial phase (PATENT-1) and an open label long-term extension trial phase In the PATENT-1 study, 443 patients with symptomatic PAH were randomized and treated with either placebo or two different dose titration arms (an individual and a capped dose titration arm) of riociguat orally over a period of 12 weeks. Riociguat was titrated over a period of eight weeks in doses of 0.5 mg increments, from 1.0 mg up to 2.5 mg three times daily or up to 1.5 mg in an exploratory arm. After the titration phase, patients were followed up for an additional four weeks on their last dose to complete PATENT-1. Patients from all three arms then had the option of participating in the open label long term extension study (PATENT-2), starting with an eight-week double-blinded sham titration. The ongoing PATENT-2 study is investigating the sustainability of the efficacy results as well as longer term safety aspects of riociguat for PAH patients. PATENT included both treatment- naïve patients and those pre-treated with an endothelin receptor antagonist (ERA) or an oral, inhaled or subcutaneous prostanoid monotherapy. PATENT-1 results
PATENT-1 met its primary end point, with riociguat shown to significantly improve exercise capacity in treatment-naïve and pre-treated patients with symptomatic PAH from baseline after 12 weeks compared with placebo. In the study, riociguat demonstrated a statistically significant improvement in the 6MWT, a marker of disease severity and a predictor of survival.9 A statistically significant improvement in exercise capacity with riociguat was observed as early as four weeks after treatment initiation and further improved in the long term extension study, PATENT-2, whilst the safety profile was sustained and confirmed.9, 14 Riociguat is the first and only oral treatment to show significant and sustained clinical efficacy in PAH in treatment-naïve as well as in patients pre-treated with ERAs or oral, inhaled or subcutaneous prostanoid monotherapy. So far no other drugs, including phosphodiesterase type 5 inhibitors (PDE5-inhibitors), have been able to show this.5, 9, 11 Additionally, statistically significant improvements were observed consistently across secondary endpoints, including PVR, NT-pro BNP, WHO FC, TTCW and Borg dyspnea score.9 The improvements in 6MWD and WHO FC observed during the pivotal 12-week PATENT-1 study were sustained during long-term extension in the PATENT-2 study for a further 12 weeks and data suggests sustained improvements over one year of observation.9, 14 Riociguat was shown to be a well-tolerated, with a good safety profile in both the CHEST and PATENT trials. Riociguat-related adverse events mostly occurring in either trial were mild or Based on the findings of CHEST and PATENT, riociguat is the first and only drug that has consistently demonstrated robust clinical efficacy in two separate PH indications: CTEPH and Taken together, the positive results of both trials, CHEST and PATENT, underline the potential of riociguat, with its unique mode of action, as an effective and well-tolerated treatment for Personalized dosing
Riociguat enables personalized oral dosing that is well supported and simply managed. It is individually titrated over the first two months of treatment, which ensures an optimized dosing scheme for patients.15 In both CHEST-1 and PATENT-1, 90% of patients received the two highest dosages of riociguat using the individual dosing scheme. Improvements were rapidly observed within the first two weeks of treatment demonstrating that even the 1 mg dose is Riociguat and Bayer HealthCare
Riociguat’s development program across different forms of PH demonstrates Bayer’s commitment to understanding this severe and life-threatening condition with the high unmet medical need to improve the lives of people with PH. Bayer is dedicated to the research and development of new, innovative treatments targeting pulmonary hypertension, building on more than 15 years’ experience with Ventavis® (iloprost) and more than a century in References
1. Ghofrani HA, Voswinckel R, Gall H et al. Riociguat for pulmonary hypertension. Future 2. Grimminger F, Weimann G, Frey R et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 2009;33(4):785-792. 3. Rosenkranz S. Pulmonary hypertension: current diagnosis and treatment. Clin Res 4. Macchia A, Marchioli R, Marfisi R et al. A meta-analysis of trials of pulmonary hypertension: a clinical condition looking for drugs and research methodology. Am Heart J 2007;153(6):1037-1047. 5. Galie N, Hoeper MM, Humbert M et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30(20):2493-2537. 6. Ali JM, Hardman G, Page A, Jenkins DP. Chronic thromboembolic pulmonary hypertension: an underdiagnosed entity? Hosp Pract (1995 ) 2012;40(3):71-79. 7. Armstrong I, Rochnia N, Harries C, Bundock S, Yorke J. The trajectory to diagnosis with pulmonary arterial hypertension: a qualitative study. BMJ Open 2012;2(2):e000806. 8. Ghofrani HA, D'Armini AM, Grimminger F et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013;369(4):319-329. 9. Ghofrani HA, Galie N, Grimminger F et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369(4):330-340. 10. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 2011;123(20):2263-2273. 11. Girgis RE. Emerging drugs for pulmonary hypertension. Expert Opin Emerg Drugs 12. Ghofrani HA, D'Armini AM, Grimminger F et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013;369(4):319-329. 13. Simonneau G, D'Armini AM, Ghofrani HA et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH): a phase III long-term extension study (CHEST-2). 5th World Sympsoium on Pulmonary Hypertension, Nice, France, 27 February - 1 March; 2013. 14. Rubin LJ, Galie N, Grimminger F et al. Safety and efficacy of riociguat for the long-term treatment of pulmonary arterial hypertension (PAH) in the phase III PATENT-2 long-term extension study. American Thoracic Society International Conference, Philadelphia, PA, USA, 17-22 May; 2013. 15. Bayer. Adempas Summary of Product Characteristics. 2013. 16. Camerini F, Alberti E, Klugmann S, Salvi A. Primary pulmonary hypertension: effects of nifedipine. Br Heart J 1980;44(3):352-356. 17. Olschewski H, Ghofrani HA, Schmehl T et al. Inhaled iloprost to treat severe pulmonary hypertension. An uncontrolled trial. German PPH Study Group. Ann Intern Med 2000;132(6):435-443.

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