The Experts below are selected from a list of 486 Experts worldwide ranked by ideXlab platform
David J. Webb - One of the best experts on this subject based on the ideXlab platform.
-
Endothelin Receptor Antagonism Improves Lipid Profiles and Lowers PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) in Patients With Chronic Kidney Disease.
Hypertension (Dallas Tex. : 1979), 2019Co-Authors: Tariq E. Farrah, David J. Webb, Robert Kimmitt, Atul Anand, Peter J. Gallacher, Edwin Carter, James W. Dear, Nicholas L. Mills, Neeraj DhaunAbstract:Dyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA (endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, Sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (-11±1%) and low-density lipoprotein-associated (-20±3%) cholesterol, lipoprotein (a) (-16±2%) and triglycerides (-20±4%); high-density lipoprotein-associated cholesterol increased (+14±2%), P
-
Selective endothelin A receptor antagonism with Sitaxentan reduces neointimal lesion size in a mouse model of intraluminal injury
British journal of pharmacology, 2015Co-Authors: Karolina M. Duthie, Patrick W. F. Hadoke, Nicholas S. Kirkby, Eileen Miller, Jessica R. Ivy, John F Mcshane, Win Gel Lim, David J. WebbAbstract:Background and Purpose Endothelin (ET) receptor antagonism reduces neointimal lesion formation in animal models. This investigation addressed the hypothesis that the selective ETA receptor antagonist Sitaxentan would be more effective than mixed ETA/B receptor antagonism at inhibiting neointimal proliferation in a mouse model of intraluminal injury. Experimental Approach Antagonism of ETA receptors by Sitaxentan (1–100 nM) was assessed in femoral arteries isolated from adult, male C57Bl6 mice using isometric wire myography. Neointimal lesion development was induced by intraluminal injury in mice receiving Sitaxentan (ETA antagonist; 15 mg·kg−1·day−1), A192621 (ETB antagonist; 30 mg·kg−1·day−1), the combination of both antagonists or vehicle. Treatment began 1 week before, and continued for 28 days after, surgery. Femoral arteries were then harvested for analysis of lesion size and composition. Key Results Sitaxentan produced a selective, concentration-dependent parallel rightward shift of ET-1-mediated contraction in isolated femoral arteries. Sitaxentan reduced neointimal lesion size, whereas ETB and combined ETA/B receptor antagonism did not. Macrophage and α-smooth muscle actin content were unaltered by ET receptor antagonism but Sitaxentan reduced the amount of collagen in lesions. Conclusions and Implications These results suggest that ETA receptor antagonism would be more effective than combined ETA/ETB receptor antagonism at reducing neointimal lesion formation.
-
Plasma pro-endothelin-1 peptide concentrations rise in chronic kidney disease and following selective endothelin A receptor antagonism.
Journal of the American Heart Association, 2015Co-Authors: Neeraj Dhaun, Iain M Macintyre, Jane Goddard, David J. Webb, Robert Kimmitt, Jale Yuzugulen, Elizabeth G. Wood, Pajaree Chariyavilaskul, Roger CorderAbstract:Background Endothelin 1 (ET‐1) contributes to chronic kidney disease (CKD) development and progression, and endothelin receptor antagonists are being investigated as a novel therapy for CKD. The proET‐1 peptides, endothelin‐like domain peptide (ELDP) and C‐terminal pro‐ET‐1 (CT‐proET‐1), are both potential biomarkers of CKD and response to therapy with endothelin antagonists. Methods and Results We assessed plasma and urine ELDP and plasma CT‐proET‐1 in CKD patients with minimal comorbidity. Next, in a randomized double‐blind crossover study of 27 subjects with proteinuric CKD, we examined the effects of 6 weeks of treatment with placebo, Sitaxentan (endothelin A antagonist), and nifedipine on these peptides alongside the primary end points of proteinuria, blood pressure, and arterial stiffness. Plasma ELDP and CT‐proET‐1 increased with CKD stage (both P
-
Endothelin antagonism and uric acid levels in pulmonary arterial hypertension: Clinical associations
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 2014Co-Authors: Neeraj Dhaun, Jeanluc Vachiery, Raymond L. Benza, Robert Naeije, Lie-ju Hwang, Xuexuan Liu, Simon Teal, David J. WebbAbstract:Background Elevated serum uric acid is detected in pulmonary arterial hypertension (PAH) and is associated with poor patient outcomes. High serum uric acid is an independent risk factor for cardiovascular disease and renal impairment. We analyzed the effects of endothelin receptor antagonism on serum uric acid in PAH patients participating in the Sitaxentan to Relieve Impaired Exercise (STRIDE)-2/2X trial, and the impact of uric acid on 6-minute walk distance (6MWD), time to clinical worsening (TtCW) and survival. Methods In the 18-week, double-blind, placebo-controlled STRIDE-2 trial, 246 PAH patients were randomized and received matched placebo, Sitaxentan 50 or 100 mg orally once daily, or open-label bosentan 125 mg twice daily. STRIDE-2X was a 1-year, open-label extension of STRIDE-2. Results Baseline serum uric acid was similar between groups. Increased serum uric acid was a significant risk factor for 1-year mortality and TtCW. Compared with placebo, Sitaxentan 50 and 100 mg and bosentan all reduced serum uric acid ( p p = 0.0037). Conclusions Endothelin receptor antagonism reduces serum uric acid in PAH patients, and this reduction is associated with improved survival and longer TtCW. Further prospective studies are needed to investigate the pathogenic role of serum uric acid in PAH and its prognostic potential.
-
Diurnal Variation in Blood Pressure and Arterial Stiffness in Chronic Kidney Disease: The Role of Endothelin-1
Hypertension (Dallas Tex. : 1979), 2014Co-Authors: Neeraj Dhaun, Iain M Macintyre, Vanessa Melville, Jane Goddard, Rebecca Moorhouse, Wilna Oosthuyzen, Robert Kimmitt, Kayleigh E. Brown, Ewan D. Kennedy, David J. WebbAbstract:Hypertension and arterial stiffness are important independent cardiovascular risk factors in chronic kidney disease (CKD) to which endothelin-1 (ET-1) contributes. Loss of nocturnal blood pressure (BP) dipping is associated with CKD progression, but there are no data on 24-hour arterial stiffness variation. We examined the 24-hour variation of BP, arterial stiffness, and the ET system in healthy volunteers and patients with CKD and the effects on these of ET receptor type A receptor antagonism (Sitaxentan). There were nocturnal dips in systolic BP and diastolic BP and pulse wave velocity, our measure of arterial stiffness, in 15 controls (systolic BP, −3.2±4.8%, P
Nazzareno Galie - One of the best experts on this subject based on the ideXlab platform.
-
corrigendum to guidelines for the diagnosis and treatment of pulmonary hypertension european heart journal 2009 30 2493 2537 the task force for the diagnosis and treatment of pulmonary hypertension of the european society of cardiology esc and the eu
European Heart Journal, 2011Co-Authors: Nazzareno Galie, Marius M Hoeper, Marc Humbert, Adam Torbicki, Jeanluc Vachiery, Joan Albert Barbera, Maurice Beghetti, P A Corris, Sean Gaine, Simon J R GibbsAbstract:The 2009 ESC Practice Clinical Guidelines for the diagnosis and treatment of pulmonary hypertension included the endothelin receptor antagonist Sitaxentan in an algorithm of evidence-based treatment for pulmonary arterial hypertension. Sitaxentan was recommended with a Class I/Level A grade of evidence in WHO functional class III patients and Class IIa/Level C grade of evidence in WHO functional clsses II and IV. Sitaxentan was initially authorized by …
-
Corrigendum to: ‘Guidelines for the diagnosis and treatment of pulmonary hypertension’ [European Heart Journal (2009) 30, 2493–2537]. The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC)
European Heart Journal, 2011Co-Authors: Nazzareno Galie, Marius M Hoeper, Marc Humbert, Adam Torbicki, Jeanluc Vachiery, Joan Albert Barbera, Maurice Beghetti, P A Corris, Sean Gaine, J. Simon R. GibbsAbstract:The 2009 ESC Practice Clinical Guidelines for the diagnosis and treatment of pulmonary hypertension included the endothelin receptor antagonist Sitaxentan in an algorithm of evidence-based treatment for pulmonary arterial hypertension. Sitaxentan was recommended with a Class I/Level A grade of evidence in WHO functional class III patients and Class IIa/Level C grade of evidence in WHO functional clsses II and IV. Sitaxentan was initially authorized by …
-
Liver toxicity of Sitaxentan in pulmonary arterial hypertension.
The European respiratory journal, 2011Co-Authors: Nazzareno Galie, Marius M Hoeper, J S R Gibbs, Gérald SimonneauAbstract:To the Editors: Ambrisentan, bosentan and Sitaxentan are endothelin receptor antagonist (ERA) drugs approved for the treatment of patients with pulmonary arterial hypertension (PAH) and are included in the treatment algorithm of the 2009 pulmonary hypertension (PH) guidelines of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) 1. Hepatotoxicity is a frequent side-effect of ERA therapy, which is contra-indicated in patients with mild to severe hepatic impairment (Child–Pugh class B–C) and elevated serum aminotransferases prior to initiation of treatment. In addition, liver function testing on a monthly basis is recommended in PAH patients treated with these compounds, in order to detect an increase in the serum aminotransferases 1. In most cases, liver injury is dose-related and reversible with dose reduction or drug discontinuation, suggesting that hepatotoxicity is caused by a dose-dependent toxic effect. The exact mechanisms by which …
-
ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities
Chest, 2006Co-Authors: Michael D Mcgoon, Chris Dufton, Michael J. Gerber, Adaani E Frost, Horst Olschewski, Vallerie V Mclaughlin, David B Badesch, Nazzareno Galie, Ronald J Oudiz, Darrin DespainAbstract:Background Some endothelin receptor antagonists (ERAs) are associated with liver function test (LFT) result abnormalities. However, ambrisentan has an incidence of serum aminotransferase levels more than three times the upper limit of normal (ULN), similar to that observed in PAH patients who are not receiving ERAs. Because ambrisentan may provide benefits in PAH patients who have discontinued ERA therapy due to LFT abnormalities, we evaluated the safety and efficacy of ambrisentan in this patient population. Methods Patients who previously discontinued bosentan and/or sitaxsentan due to LFT abnormalities received ambrisentan, 2.5 mg qd, for 4 weeks followed by 5 mg/d for 8 weeks. The primary end point was the incidence of aminotransferase levels more than three times ULN considered by the investigator to be related to ambrisentan and resulting in drug discontinuation. Secondary end points included aminotransferase levels more than five times ULN requiring drug discontinuation and more than three times ULN requiring dose reduction, as well as changes in 6-min walk distance (6MWD), Borg dyspnea index, World Health Organization functional class, and Short Form-36 health survey score. Patients continued treatment beyond the 12-week end point with monthly monitoring of LFTs. Results Thirty-six patients who previously discontinued bosentan (n = 31), sitaxsentan (n = 2), or both (n = 3) were enrolled. At baseline, 69.4% of patients were receiving prostanoid and/or sildenafil therapy. No patient had an aminotransferase level more than three times ULN that required ambrisentan discontinuation. One patient had a transient aminotransferase level more than three times ULN that resolved following a temporary dose reduction. No additional aminotransferase levels more than three times ULN were observed with long-term treatment (median exposure, 102 weeks), despite dose increases to 10 mg qd in more than half of the patients. Significant improvements in 6MWD and other efficacy assessments were observed. Conclusions Ambrisentan treatment may be an option for patients who have discontinued bosentan and/or sitaxsentan therapy due to LFT result abnormalities. Trial registration Clinicaltrials.gov Identifier NCT00423592.
-
Pulmonary arterial hypertension associated to connective tissue diseases.
Lupus, 2005Co-Authors: Nazzareno Galie, Alessandra Manes, K V Farahani, F Pelino, Massimiliano Palazzini, Luca Negro, Serena Romanazzi, Angelo BranziAbstract:Pulmonary arterial hypertension is a well-known complication of connective tissue diseases such as systemic sclerosis, systemic lupus erythematosus, mixed connective tissue diseases, and to a lesser extent, rheumatoid arthritis, dermatopolymyositis and primary Sjogren's syndrome. In these patients, pulmonary hypertension may occur in association with left heart disease, interstitial fibrosis or as a result of a isolated pulmonary arteriopathy. The incidence of pulmonary arterial hypertension in the limited form of systemic sclerosis is about 10%. The pathophysiologic mechanisms leading to pulmonary arterial hypertension remain unknown. Symptoms and clinical presentation are very similar to idiopathic pulmonary arterial hypertension but mortality was confirmed to be higher. Echocardiography is the reference investigation for the detection of pulmonary arterial hypertension but the results should be confirmed by right heart catheterization. Treatment appears more complex as compared to idiopathic pulmonary arterial hypertension. Intravenous epoprostenol therapy has been shown to be effective in a special trail. Also, the endothelin receptor antagonists bosentan and Sitaxentan, the phosphodyesterase-type-5 sildenafil and subcutaneous treprostinil have shown favourable results.
Neeraj Dhaun - One of the best experts on this subject based on the ideXlab platform.
-
Endothelin Receptor Antagonism Improves Lipid Profiles and Lowers PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) in Patients With Chronic Kidney Disease.
Hypertension (Dallas Tex. : 1979), 2019Co-Authors: Tariq E. Farrah, David J. Webb, Robert Kimmitt, Atul Anand, Peter J. Gallacher, Edwin Carter, James W. Dear, Nicholas L. Mills, Neeraj DhaunAbstract:Dyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA (endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, Sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (-11±1%) and low-density lipoprotein-associated (-20±3%) cholesterol, lipoprotein (a) (-16±2%) and triglycerides (-20±4%); high-density lipoprotein-associated cholesterol increased (+14±2%), P
-
Plasma pro-endothelin-1 peptide concentrations rise in chronic kidney disease and following selective endothelin A receptor antagonism.
Journal of the American Heart Association, 2015Co-Authors: Neeraj Dhaun, Iain M Macintyre, Jane Goddard, David J. Webb, Robert Kimmitt, Jale Yuzugulen, Elizabeth G. Wood, Pajaree Chariyavilaskul, Roger CorderAbstract:Background Endothelin 1 (ET‐1) contributes to chronic kidney disease (CKD) development and progression, and endothelin receptor antagonists are being investigated as a novel therapy for CKD. The proET‐1 peptides, endothelin‐like domain peptide (ELDP) and C‐terminal pro‐ET‐1 (CT‐proET‐1), are both potential biomarkers of CKD and response to therapy with endothelin antagonists. Methods and Results We assessed plasma and urine ELDP and plasma CT‐proET‐1 in CKD patients with minimal comorbidity. Next, in a randomized double‐blind crossover study of 27 subjects with proteinuric CKD, we examined the effects of 6 weeks of treatment with placebo, Sitaxentan (endothelin A antagonist), and nifedipine on these peptides alongside the primary end points of proteinuria, blood pressure, and arterial stiffness. Plasma ELDP and CT‐proET‐1 increased with CKD stage (both P
-
Endothelin antagonism and uric acid levels in pulmonary arterial hypertension: Clinical associations
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 2014Co-Authors: Neeraj Dhaun, Jeanluc Vachiery, Raymond L. Benza, Robert Naeije, Lie-ju Hwang, Xuexuan Liu, Simon Teal, David J. WebbAbstract:Background Elevated serum uric acid is detected in pulmonary arterial hypertension (PAH) and is associated with poor patient outcomes. High serum uric acid is an independent risk factor for cardiovascular disease and renal impairment. We analyzed the effects of endothelin receptor antagonism on serum uric acid in PAH patients participating in the Sitaxentan to Relieve Impaired Exercise (STRIDE)-2/2X trial, and the impact of uric acid on 6-minute walk distance (6MWD), time to clinical worsening (TtCW) and survival. Methods In the 18-week, double-blind, placebo-controlled STRIDE-2 trial, 246 PAH patients were randomized and received matched placebo, Sitaxentan 50 or 100 mg orally once daily, or open-label bosentan 125 mg twice daily. STRIDE-2X was a 1-year, open-label extension of STRIDE-2. Results Baseline serum uric acid was similar between groups. Increased serum uric acid was a significant risk factor for 1-year mortality and TtCW. Compared with placebo, Sitaxentan 50 and 100 mg and bosentan all reduced serum uric acid ( p p = 0.0037). Conclusions Endothelin receptor antagonism reduces serum uric acid in PAH patients, and this reduction is associated with improved survival and longer TtCW. Further prospective studies are needed to investigate the pathogenic role of serum uric acid in PAH and its prognostic potential.
-
Diurnal Variation in Blood Pressure and Arterial Stiffness in Chronic Kidney Disease: The Role of Endothelin-1
Hypertension (Dallas Tex. : 1979), 2014Co-Authors: Neeraj Dhaun, Iain M Macintyre, Vanessa Melville, Jane Goddard, Rebecca Moorhouse, Wilna Oosthuyzen, Robert Kimmitt, Kayleigh E. Brown, Ewan D. Kennedy, David J. WebbAbstract:Hypertension and arterial stiffness are important independent cardiovascular risk factors in chronic kidney disease (CKD) to which endothelin-1 (ET-1) contributes. Loss of nocturnal blood pressure (BP) dipping is associated with CKD progression, but there are no data on 24-hour arterial stiffness variation. We examined the 24-hour variation of BP, arterial stiffness, and the ET system in healthy volunteers and patients with CKD and the effects on these of ET receptor type A receptor antagonism (Sitaxentan). There were nocturnal dips in systolic BP and diastolic BP and pulse wave velocity, our measure of arterial stiffness, in 15 controls (systolic BP, −3.2±4.8%, P
-
Endothelin-A Receptor Antagonism Modifies Cardiovascular Risk Factors in CKD
Journal of the American Society of Nephrology : JASN, 2012Co-Authors: Neeraj Dhaun, Vanessa Melville, Neil R. Johnston, Jane Goddard, Scott Blackwell, Dinesh Talwar, David J. WebbAbstract:Arterial stiffness and impaired nitric oxide (NO) bioavailability contribute to the high risk for cardiovascular disease in CKD. Both asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO production, and endothelin-1 (ET-1) oppose the actions of NO, suggesting that ET-1 receptor antagonists may have a role in cardiovascular protection in CKD. We conducted a randomized, double-blind, three-way crossover study in 27 patients with proteinuric CKD to compare the effects of the ET A receptor antagonist Sitaxentan, nifedipine, and placebo on proteinuria, BP, arterial stiffness, and various cardiovascular biomarkers. After 6 weeks of treatment, placebo and nifedipine did not affect plasma urate, ADMA, or urine ET-1/creatinine, which reflects renal ET-1 production; in contrast, Sitaxentan led to statistically significant reductions in all three of these biomarkers. No treatment affected plasma ET-1. Reductions in proteinuria and BP after Sitaxentan treatment was associated with increases in urine ET-1/creatinine, whereas reduction in pulse-wave velocity, a measure of arterial stiffness, was associated with a decrease in ADMA. Taken together, these data suggest that ET A receptor antagonism may modify risk factors for cardiovascular disease in CKD.
Marius M Hoeper - One of the best experts on this subject based on the ideXlab platform.
-
corrigendum to guidelines for the diagnosis and treatment of pulmonary hypertension european heart journal 2009 30 2493 2537 the task force for the diagnosis and treatment of pulmonary hypertension of the european society of cardiology esc and the eu
European Heart Journal, 2011Co-Authors: Nazzareno Galie, Marius M Hoeper, Marc Humbert, Adam Torbicki, Jeanluc Vachiery, Joan Albert Barbera, Maurice Beghetti, P A Corris, Sean Gaine, Simon J R GibbsAbstract:The 2009 ESC Practice Clinical Guidelines for the diagnosis and treatment of pulmonary hypertension included the endothelin receptor antagonist Sitaxentan in an algorithm of evidence-based treatment for pulmonary arterial hypertension. Sitaxentan was recommended with a Class I/Level A grade of evidence in WHO functional class III patients and Class IIa/Level C grade of evidence in WHO functional clsses II and IV. Sitaxentan was initially authorized by …
-
Corrigendum to: ‘Guidelines for the diagnosis and treatment of pulmonary hypertension’ [European Heart Journal (2009) 30, 2493–2537]. The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC)
European Heart Journal, 2011Co-Authors: Nazzareno Galie, Marius M Hoeper, Marc Humbert, Adam Torbicki, Jeanluc Vachiery, Joan Albert Barbera, Maurice Beghetti, P A Corris, Sean Gaine, J. Simon R. GibbsAbstract:The 2009 ESC Practice Clinical Guidelines for the diagnosis and treatment of pulmonary hypertension included the endothelin receptor antagonist Sitaxentan in an algorithm of evidence-based treatment for pulmonary arterial hypertension. Sitaxentan was recommended with a Class I/Level A grade of evidence in WHO functional class III patients and Class IIa/Level C grade of evidence in WHO functional clsses II and IV. Sitaxentan was initially authorized by …
-
Liver toxicity of Sitaxentan in pulmonary arterial hypertension.
The European respiratory journal, 2011Co-Authors: Nazzareno Galie, Marius M Hoeper, J S R Gibbs, Gérald SimonneauAbstract:To the Editors: Ambrisentan, bosentan and Sitaxentan are endothelin receptor antagonist (ERA) drugs approved for the treatment of patients with pulmonary arterial hypertension (PAH) and are included in the treatment algorithm of the 2009 pulmonary hypertension (PH) guidelines of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) 1. Hepatotoxicity is a frequent side-effect of ERA therapy, which is contra-indicated in patients with mild to severe hepatic impairment (Child–Pugh class B–C) and elevated serum aminotransferases prior to initiation of treatment. In addition, liver function testing on a monthly basis is recommended in PAH patients treated with these compounds, in order to detect an increase in the serum aminotransferases 1. In most cases, liver injury is dose-related and reversible with dose reduction or drug discontinuation, suggesting that hepatotoxicity is caused by a dose-dependent toxic effect. The exact mechanisms by which …
-
Liver toxicity: the Achilles' heel of endothelin receptor antagonist therapy?
The European respiratory journal, 2009Co-Authors: Marius M HoeperAbstract:The medical community has been alerted by case reports of serious liver injury associated with Sitaxentan, an endothelin receptor antagonist (ERA) used for the treatment of pulmonary arterial hypertension (PAH). The first of these case reports was published in the June issue of the European Respiratory Journal and described a patient with PAH who was initially treated with bosentan, another ERA 1. This treatment was stopped after 6 months because of an increase in liver aminotransferases. The liver enzymes quickly returned to normal upon withdrawal of bosentan and, a few months later, Sitaxentan therapy was started. Four months after this, liver aminotransferases started to increase again and the drug was discontinued, but the liver enzymes continued to rise to almost 1,000 U·L−1 and the patient developed mild hyperbilirubinemia. Under the assumption of a drug-related idiosyncratic reaction, corticosteroid therapy was initiated resulting in prompt and sustained normalisation of liver enzymes. In the present issue of the European Respiratory Journal , Lavelle et al . 2 from Dublin, Ireland report on two perturbing cases of severe liver toxicity that developed 3 and 4 months, respectively, after Sitaxentan therapy had been initiated. These patients showed severe liver dysfunction, with markedly elevated bilirubin levels >300 μmol·L−1 and elevated prothrombin times. In both patients, liver biopsies showed extensive hepatocellular damage and infiltrates of eosinophils and lymphocytes. As in the first case, liver function deteriorated for several weeks after discontinuation of Sitaxentan. Corticosteroid therapy was not attempted. One of these patients recovered slowly, the …
-
Severe hepatitis associated with Sitaxentan and response to glucocorticoid therapy.
The European respiratory journal, 2009Co-Authors: Marius M Hoeper, Karen M. Olsson, Andrea Schneider, Heiko GolponAbstract:To the Editors: Endothelin receptor antagonists (ERA) have become standard therapy for patients with pulmonary arterial hypertension (PAH), next to phosphodiesterase-5 inhibitors and prostanoids 1–3. One of the most common side-effects associated with ERA therapy is hepatotoxicity, usually detected by an increase in the serum aminotransferases 1, 4. The underlying mechanism may be related to inhibition of a bile-salt transporter pump 5. The typical pattern of this type of liver injury is that of a toxic mechanism, i.e. dose-related and rapidly reversible upon dose reduction or drug withdrawal. Herein, we present a case of liver injury associated with the ERA Sitaxentan, which showed a different pattern in that liver injury worsened despite drug discontinuation and aminotransferases normalised after glucocorticoid therapy had been initiated, raising the hypothesis that hepatotoxicity might have been related to an idiosyncratic, i.e. immune-mediated, mechanism. The patient, a 25-yr-old female (height: 178 cm; weight: 58 kg) with Eisenmenger's …
Angelo Branzi - One of the best experts on this subject based on the ideXlab platform.
-
Pulmonary arterial hypertension associated to connective tissue diseases.
Lupus, 2005Co-Authors: Nazzareno Galie, Alessandra Manes, K V Farahani, F Pelino, Massimiliano Palazzini, Luca Negro, Serena Romanazzi, Angelo BranziAbstract:Pulmonary arterial hypertension is a well-known complication of connective tissue diseases such as systemic sclerosis, systemic lupus erythematosus, mixed connective tissue diseases, and to a lesser extent, rheumatoid arthritis, dermatopolymyositis and primary Sjogren's syndrome. In these patients, pulmonary hypertension may occur in association with left heart disease, interstitial fibrosis or as a result of a isolated pulmonary arteriopathy. The incidence of pulmonary arterial hypertension in the limited form of systemic sclerosis is about 10%. The pathophysiologic mechanisms leading to pulmonary arterial hypertension remain unknown. Symptoms and clinical presentation are very similar to idiopathic pulmonary arterial hypertension but mortality was confirmed to be higher. Echocardiography is the reference investigation for the detection of pulmonary arterial hypertension but the results should be confirmed by right heart catheterization. Treatment appears more complex as compared to idiopathic pulmonary arterial hypertension. Intravenous epoprostenol therapy has been shown to be effective in a special trail. Also, the endothelin receptor antagonists bosentan and Sitaxentan, the phosphodyesterase-type-5 sildenafil and subcutaneous treprostinil have shown favourable results.
-
Emerging medical therapies for pulmonary arterial hypertension.
Progress in cardiovascular diseases, 2002Co-Authors: Nazzareno Galie, Alessandra Manes, Angelo BranziAbstract:Until a few years ago, "conventional" treatment for pulmonary arterial hypertension (PAH) included oral anticoagulants, calcium channel blockers, diuretics, digoxin, and oxygen. In the 1990s, 3 randomized studies demonstrated that the continuous intravenous infusion of epoprostenol improved functional capacity, cardiopulmonary hemodynamics, and survival in patients with severe PAH. Recently, the thromboxane inhibitor terbogrel, the prostacyclin analogues treprostinil, beraprost, and iloprost, and the endothelin receptor antagonist bosentan have been tested in clinical trials in more than 1,100 patients. Except for terbogrel, all compounds have improved by different degrees the mean exercise capacity as assessed by 6 minutes walking distance. Conversely, these trials differ for the severity and etiology of included PAH patients as well as for the effects on combined clinical events, on quality of life, and on hemodynamics. No trials have shown effects on mortality, and each new compound presents different side effects that seem unpredictable in the individual patient. At present, additional new compounds such as Sitaxentan, ambisentan, L-arginine, and sildenafil are studied in clinical trials. The new therapeutic options are currently in different phases of approval by regulatory agencies, and when they will become available we will have the opportunity to select the most appropriate treatment for the single patient, according to an individualized benefit-to-risk ratio.