lu-208075 and Edema

Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH.. To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial.. This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response).. In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups.. This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy.. NCT01178073, post results.

Topics: Adult; Aged; Antihypertensive Agents; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Edema; Female; Humans; Hypertension, Pulmonary; Lupus Erythematosus, Systemic; Male; Middle Aged; Mixed Connective Tissue Disease; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pyridazines; Scleroderma, Systemic; Tadalafil

Edema is a common side effect of endothelin receptor antagonists. Ambrisentan is an endothelin type A-selective endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension. We examined the clinical outcomes of patients who developed edema with and without ambrisentan treatment in 2 phase III, randomized placebo-controlled trials, ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2 (ARIES-1 and ARIES-2) (n = 393). Edema-related adverse events were extracted using broad adverse event search terms. The present post hoc analysis included 132 placebo patients and 261 ambrisentan patients. Of these patients, 14% of the placebo patients and 23% of the ambrisentan patients experienced edema-related adverse events. Overall, the patients who experienced edema tended to have a worse baseline World Health Organization (WHO) functional class (edema 76%, WHO functional class III-IV; no edema 56%, WHO functional class III-IV). In the ambrisentan patients, those with edema were older (mean age 58 ± 13 years) and heavier (mean weight 75 ± 19 kg) than those without edema (mean age 49 ± 15 years; mean weight 70 ± 17 kg). At week 12 of treatment, the ambrisentan patients had significantly increased their 6-minute walk distance (6MWD) by 34.4 m compared to the placebo patients in whom the 6MWD had deteriorated by -9.0 m (p <0.001). Among the ambrisentan patients, those without edema had a 6MWD increase of 38.9 m and those with edema had a 6MWD increase of 19.4 m. Ambrisentan significantly improved the brain natriuretic peptide levels by -34% compared to the brain natriuretic peptide levels in the placebo group that had worsened by +11% (p <0.001). Ambrisentan reduced the brain natriuretic peptide concentrations similarly in patients with and without edema. In conclusion, the present subanalysis of patients with pulmonary arterial hypertension has revealed that ambrisentan therapy provides clinical benefit compared to placebo, even in the presence of edema.

Topics: Adult; Age Factors; Aged; Analysis of Variance; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Edema; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Incidence; Male; Middle Aged; Natriuretic Peptide, Brain; Phenylpropionates; Pyridazines; Reference Values; Risk Assessment; Safety Management; Severity of Illness Index; Sex Factors; Treatment Outcome

Pulmonary arterial hypertension (PAH) is an intractable and rare disease and the accumulation of clinical evidence under real-world setting is needed. A post-marketing surveillance for the endothelin receptor antagonist ambrisentan (Volibris tablet) has been conducted by all-case investigation since September 2010. This paper is an interim report on the safety and efficacy of ambrisentan in 702 patients with PAH.. PAH patients aged 15 years or older were subjected to the analysis. The safety analysis by overall cases or stratification of patient backgrounds and the efficacy analysis were investigated.. Regarding patient characteristics, the 702 patients subjected to safety analysis included 543 (77.4%) women and 546 (77.8%) patients at WHO functional class II/III. The mean observational time was 392.7 days. A total of 324 adverse drug reaction (ADR) occurred in 204 (29.1%) patients. Common ADRs (≥ 2%) included anemia (4.6%), peripheral edema (4.1%), headache (3.6%), edema and face edema (2.6% each), abnormal hepatic function (2.3%), and epistaxis (2.1%). There were 82 serious ADRs occurring in 44 (6.3%) patients (385 serious adverse events in 184 (26.2%) patients). Although 11 (1.6%) interstitial lung disease (ILD) cases were reported, all were observed in patients with disease that may contribute to ILD and therefore it is difficult to assess if ambrisentan was associated with these events. There was no difference in safety in relation to the presence/absence of connective tissue disease-related PAH (CTD-PAH) or combination therapy. Among 677 patients subjected to efficacy analysis, those in whom hemodynamic status was determined before and after treatment showed improvement in the mean pulmonary arterial pressure and pulmonary vascular resistance after treatment.. The interim results showed safety consistent with the known profile of ambrisentan in terms of the types and frequencies of ADRs in patients with PAH in real clinical practice, in comparison with previous clinical trials in Japan and the rest of the world. Thus, these results provided another corroboration of the tolerability of ambrisentan and we continue to monitor proper use information via the post-marketing surveillance to ensure any new safety signals are identified in a timely manner (ClinTrial.gov: NCT01406327).

Topics: Adult; Aged; Antihypertensive Agents; Edema; Endothelin Receptor Antagonists; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Japan; Male; Middle Aged; Phenylpropionates; Product Surveillance, Postmarketing; Pyridazines; Research Report; Tablets; Treatment Outcome

Endothelin-1 binding to endothelin A receptors (ETA) elicits profibrogenic, proinflammatory, and proliferative effects that can promote a wide variety of diseases. Although ETA antagonists are approved for the treatment of pulmonary hypertension, their clinical utility in several other diseases has been limited by fluid retention. ETA blocker-induced fluid retention could be due to inhibition of ETA activation in the heart, vasculature, and/or kidney; consequently, the current study was designed to define which of these sites are involved. Mice were generated with absence of ETA specifically in cardiomyocytes (heart), smooth muscle, the nephron, the collecting duct, or no deletion (control). Administration of the ETA antagonist ambrisentan or atrasentan for 2 weeks caused fluid retention in control mice on a high-salt diet as assessed by increases in body weight, total body water, and extracellular fluid volume (using impedance plethysmography), as well as decreases in hematocrit (hemodilution). Mice with heart ETA knockout retained fluid in a similar manner as controls when treated with ambrisentan or atrasentan. Mice with smooth muscle ETA knockout had substantially reduced fluid retention in response to either ETA antagonist. Mice with nephron or collecting duct ETA disruption were completely prevented from ETA blocker-induced fluid retention. Taken together, these findings suggest that ETA antagonist-induced fluid retention is due to a direct effect of this class of drug on the collecting duct, is partially related to the vascular action of the drugs, and is not due to alterations in cardiac function.

Topics: Animals; Atrasentan; Body Fluids; Edema; Endothelin A Receptor Antagonists; Kidney Tubules, Collecting; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Myocardium; Nephrons; Organ Specificity; Phenylpropionates; Pyridazines; Pyrrolidines; Receptor, Endothelin A; Sodium Chloride, Dietary; Species Specificity

Currently available endothelin receptor antagonists for treating pulmonary arterial hypertension block either the endothelin (ET) receptor A or both A and B receptors. Transition from one endothelin receptor antagonist to another may theoretically alter side-effects or efficacy. We report our experience of a transition from sitaxsentan to ambrisentan, both predominant ET(A) receptor antagonists, in pulmonary arterial hypertension patients.. At Baylor Pulmonary Hypertension Center, 18 patients enrolled in the open-label extension phase of the original sitaxsentan studies (Sitaxsentan To Relieve ImpaireD Exercise) were transitioned to ambrisentan (from July 2007 to September 2007) at the time of study closure. Pre-transition (PreT), 1 month (1Mth) and 1 year (1Yr) post-transition assessments of 6-minute walk distance (6MWD), brain naturetic peptide (BNP) levels, WHO functional class (WHO FC), Borg dyspnea score (BDS), oxygen saturation, liver function, and peripheral edema were compared.. 6MWD was 356 ± 126 m at PreT, 361 ± 125 m at 1Mth, and 394 ± 114 m at 1Yr (mean ± SD). There was no difference in the walk distance at 1Mth and 1Yr post transition compared with PreT (P=0.92, 0.41 respectively). Oxygen saturation was no different at 1Mth and 1Yr to PreT level (P=0.49 and P=0.06 respectively). BNP was 178 ± 44 pg/mL at PreT, 129 ± 144 pg/mL at 1Mth and 157 ± 201 at 1Yr. Peripheral edema was present in 7/18 patients at PreT, in 8/16 patients at 1Mth, and in 6/13 patients at 1Yr post transition. Proportions of patients with edema over these 3 time points did not change significantly (P=0.803). At 1Yr, 2 patients had died, 1 had undergone lung transplantation, 1 had relocated, and 1 patient was started on intravenous prostacyclin therapy. Over 3 points (baseline, 1 month, and 1 year), there was no significant change in function class (P=0.672).. Our limited data suggest that ET(A) receptor antagonists can be switched from one to another with sustained exercise capacity and maintained WHO FC with no increase in incidence of peripheral edema.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Drug Substitution; Dyspnea; Edema; Endothelin A Receptor Antagonists; Exercise Test; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Isoxazoles; Liver Function Tests; Male; Middle Aged; Natriuretic Peptide, Brain; Oxygen; Phenylpropionates; Pyridazines; Retrospective Studies; Texas; Thiophenes; Time Factors; Treatment Outcome; Walking

Endothelins are involved in tissue inflammation, pain, edema and cell migration. Our genome-wide microarray analysis revealed that endothelin-1 (ET-1) and endothelin-2 (ET-2) showed a marked up-regulation in dorsal root ganglia during the acute phase of arthritis. We therefore examined the effects of endothelin receptor antagonists on the development of arthritis and inflammatory pain in monoarthritic mice.. Gene expression was examined in lumbar dorsal root ganglia two days after induction of antigen-induced arthritis (AIA) using mRNA microarray analysis. Effects of drug treatment were determined by repeated assessment of joint swelling, pain-related behavior, and histopathological manifestations during AIA.. Daily oral administration of the mixed ET(A) and ET(B) endothelin receptor antagonist bosentan significantly attenuated knee joint swelling and inflammation to an extent that was comparable to dexamethasone. In addition, bosentan reduced inflammatory mechanical hyperalgesia. Chronic bosentan administration also inhibited joint swelling and protected against inflammation and joint destruction during AIA flare-up reactions. In contrast, the ET(A)-selective antagonist ambrisentan failed to promote any detectable antiinflammatory or antinociceptive activity.. Thus, the present study reveals a pivotal role for the endothelin system in the development of arthritis and arthritic pain. We show that endothelin receptor antagonists can effectively control inflammation, pain and joint destruction during the course of arthritis. Our findings suggest that the antiinflammatory and antinociceptive effects of bosentan are predominantly mediated via the ET(B) receptor.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Arthralgia; Arthritis, Experimental; Bosentan; Disease Models, Animal; Edema; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Female; Ganglia, Spinal; Mice; Mice, Inbred C57BL; Nociception; Phenylpropionates; Pyridazines; Secondary Prevention; Sulfonamides