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The management of pulmonary arterial hypertension (PAH) has become more complex in recent years because of increased pharmacotherapy options and longer patient survival with increasing numbers of comorbidities. As such, more opportunities exist for drug-drug interactions between PAH-targeted medications and medications potentially used to treat comorbid conditions. In this review, we provide an overview of pharmaceutical metabolism by cytochrome P450 and discuss important drug-drug interactions for the 14 Food and Drug Administration-approved medications for PAH in the nitric oxide (NO), endothelin, and prostacyclin pathways. Among the targets in the NO pathway (sildenafil, tadalafil, and riociguat), important interactions with nitrates, protease inhibitors, and other phosphodiesterase inhibitors can cause profound hypotension. In the endothelin pathway, bosentan is associated with more drug interactions via CYP3A4 inhibition; macitentan and ambrisentan have fewer interactions of note. Although the parenteral therapies in the prostacyclin pathway bypass significant liver metabolism and avoid drug interactions, selexipag and oral treprostinil may exhibit interactions with CYP2C8 inhibitors such as gemfibrozil and clopidogrel, which can raise drug levels. Finally, we provide a framework for identifying potential drug-drug interactions and avoiding errors.

Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes. Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.

Although pulmonary endarterectomy (PEA) is the treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH), many patients have inoperable disease, and some have persistent or recurrent pulmonary hypertension (PH) after surgery. Alternative options (balloon pulmonary angioplasty (BPA) and PH-targeted medical therapy) are, therefore, required. Studies of medical therapies for CTEPH have evolved since Aerosolized Iloprost Randomized (AIR), the first randomized, controlled study of a PH-targeted therapy (inhaled iloprost) to include patients with CTEPH. Key learnings from these studies include the need to evaluate CTEPH separately from other types of PH, the importance of prospective operability adjudication as part of the protocol, and the need for sufficient duration to allow treatment benefits to become apparent. The 16-week Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Study 1 (CHEST-1) study was the first to operationalize these learnings, demonstrating a significant mean improvement in 6-minute walk distance (+46 m) and improvements in hemodynamic endpoints with riociguat versus placebo. Findings from previous studies will inform the design of future studies to address key issues related to combination medical therapy. Data on combinations of macitentan with phosphodiesterase type 5 inhibitors or oral prostanoids are available from MERIT, the first study to allow such regimens. No data on combinations including riociguat, the only licensed medical therapy for CTEPH, are available. Studies are also needed for multimodality treatment, including medical therapy plus BPA, and medical therapy as a bridge to PEA in selected operable patients. To address these issues and improve patient outcomes, it is vital that we learn from current studies to improve future trial design.

This article summarizes the likely attenuation properties of RRx-001 in COVID-19 based on its mechanism of action and the putative pathogenesis of the disease, which appears to activate inflammatory, oxidative, and immune cascades with the potential to culminate in acute respiratory distress syndrome, cytokine storm and death. An ongoing pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19 appears to present with 3 major patterns of clinical symptomatology: (1) mild upper respiratory tract infection, (2) non-life-threatening pneumonia, and (3) severe pneumonia and acute respiratory distress syndrome that initially manifest as a mild prodrome lasting for 7-8 days before rapid clinical and radiological deterioration requiring ICU transfer. RRx-001 is a targeted nitric oxide donor. This small molecule, which has been evaluated in multiple Phase 1-2 clinical trials for cancer as well as a Phase 3 clinical trial for the treatment of small cell lung cancer called REPLATINUM (NCT03699956), is minimally toxic and demonstrates clear evidence of antitumor activity. During the course of these clinical trials it was noted that the rate of chronic obstructive pulmonary disease exacerbation and pneumonia in actively smoking small cell lung cancer patients treated with RRx-001 is less than 1%. Due to extensive history of tobacco use, 40%-70% of patients with lung cancer have chronic obstructive pulmonary disease and the expected rate of pulmonary infection in this population is 50%-70%, which was not observed in RRx-001 clinical trials. Moreover, in preclinical studies of pulmonary hypertension, RRx-001 was found to be comparable with or more effective than the FDA approved agent, Bosentan. The potential pulmonary protective effects of RRx-001 in patients with recurrent lung infections coupled with preclinical models demonstrating RRx-001-mediated reversal of pulmonary hypertension suggests RRx-001 may have therapeutic activity in patients wit

The phase 4 COMPASS-3 study evaluated whether a singular endpoint produces clinically meaningful outcomes in patients with pulmonary arterial hypertension (PAH). The relationship between cardiac magnetic resonance imaging (cMRI)-derived parameters and right heart catheterization (RHC) measurements was also examined. In COMPASS-3 (ClinicalTrials.gov NCT00433329), 100 patients with PAH received bosentan monotherapy for 16 weeks. Patients continued monotherapy if their 6-min walk distance (6MWD) was ≥380 m, or otherwise received add-on sildenafil for an additional 12 weeks. 6MWD, RHC, and cMRI were performed at baseline, week 16, and week 28 (6MWD and cMRI). Baseline median 6MWD was 274 m and 82% of patients had WHO Functional Class III/IV. At week 16, 17% (n = 16) of remaining patients achieved the 6MWD threshold and 78 (83%) did not. In the intention-to-treat population, median 6MWD increased significantly relative to baseline (week 16 = 308 m; week 28 = 327 m; P < 0.001). At week 28, 9/16 (monotherapy) and 15/76 (20%; add-on sildenafil) patients met the target threshold. Baseline cMRI-derived and RHC-derived parameters showed moderate-to-strong correlations (e.g. right to left ventricular end-diastolic ratio [RVEDV:LVEDV] correlated strongly with pulmonary vascular resistance [r = +0.729, P < 0.0001]). cMRI-derived parameters predicted clinical worsening/decline (e.g. week 16 RVEDV:LVDEV [ P = 0.0172]). Time to clinical worsening/decline did not differ between patients based on 6MWD threshold achievement. No unexpected safety events were reported. A substantial proportion of patients failed to achieve the goal of 380 m, regardless of treatment. Several cMRI parameters predicted clinical worsening/decline and its non-invasive nature further supports its use in future clinical trials.

The aim of this paper is the review of literature data about effectiveness and safety of bosentan in the treatment of pulmonary hypertension. In addition, it considers some aspects of diagnosis, classification and pathogenesis of pulmonary hypertension. It is concluded that bosentan is effective both as monotherapy and in combination therapy of patients with pulmonary arterial hypertension. In patients with chronic thromboembolic pulmonary hypertension, it is possible to use bosentan, but positive changes are less significant than in patients with pulmonary arterial hypertension. Data about possible adverse effects of bosentan and ways to avoid them are considered., Целью данной статьи был обзор данных литературы относительно эффективности и безопасности применения бозентана в лечении легочной гипертензии. Кроме того, освещаются вопросы диагностики, классификации и патогенеза легочной гипертензии. Автор делает вывод, что бозентан является достаточно эффективным препаратом как в монотерапии, так и в составе комбинированной терапии пациентов с легочной артериальной гипертензией. При хронической тромбоэмболической легочной гипертензии применение бозентана возможно, но положительные изменения являются не такими выраженными, как у пациентов с легочной артериальной гипертензией. Рассматриваются данные литературы о возможных побочных явлениях бозентана и способах их избежать., Метою даної статті був огляд даних літератури щодо ефективності та безпечності застосування бозентану в лікуванні легеневої гіпертензії. Окрім того, висвітлюються питання діагностики, класифікації та патогенезу легеневої гіпертензії. Автор дійшов висновку, що бозентан є достатньо ефективним препаратом як у монотерапії, так і в складі комбінованої терапії пацієнтів із легеневою артеріальною гіпертензією. При хронічній тромбоемболічній легеневій гіпертензії застосування бозентану є можливим, але позитивні зміни не є такими вираженими, як у пацієнтів із легеневою артеріальною гіпертензією. Розглядаються дані літератури щодо можливих побічних явищ бозентану та способів їх уникнути.

Oxygen plays a central role in cardiac energy metabolism. At high altitude where the ambient oxygen level is low, we found EDNRB is associated with human hypoxia adaptation. Our subsequent study in global heterozygous knockout mice (Ednrb-/+) revealed that cardiac function was conserved in these mice when exposed to extreme hypoxia. The major goal of this study was (i) to determine the functional role of cardiomyocyte EdnrB in maintaining cardiac function under hypoxic stress and (ii) to validate the phenotypes we detected in Ednrb-/+ mice using EDNRB blockers. Unlike the global knockouts, cardiac-specific heterozygote (EdnrBflox/+) and homozygote (EdnrBflox/flox) EdnrB knockout mice were phenotypically normal. When treated with graded low levels of oxygen (10% and 5% O2), both EdnrBflox/+ and EdnrBflox/flox were hypoxia tolerant. The cardiac indexes at 10% and 5% O2 for EdnrBflox/+ were significantly higher and lactate levels were significantly lower when compared to the cre-negative controls (P < 0.05). Simultaneously, mice treated with BQ-788 (EDNRB-specific blocker) had a significantly higher cardiac index (P < 0.005) and significantly lower lactate levels (P < 0.0001) than in control mice. A similar result was obtained with mice treated with Bosentan (non-specific). These data indicate that a lower level or complete lack of EdnrB in the cardiomyocytes significantly improves cardiac performance under extreme hypoxia, a novel role of cardiomyocyte EdnrB in the regulation of cardiac function. Furthermore, this rescue under extreme hypoxia can also be achieved using EDNRB-specific pharmacological agents, e.g., BQ-788. This systematically confirms, both genetically and pharmacologically, the protective role of a lower EDNRB under extreme hypoxia stress.Key messagesUnder normal condition, cardiomyocytes-specific EdnrB knockout mice, both heterozygote and homozygote, are phenotypically normal. Under hypoxic condition, a lower level or complete deletion of car

TECCHIO, CRISTINA, 4415, open, Multiple Myeloma (MM) is a monoclonal tumor of bone marrow (BM) plasma cell (PC), usually associated with a number of disease manifestations, including skeletal damage, anemia and immunosuppression. Despite recent therapeutic advances and an increased patient life expectancy, MM still remains an incurable malignancy. MM PC is characterized by a strong BM niche dependence, acquiring an autonomous capacity of growth only in the latter stages of disease. The endothelin (ET) axis is mainly composed of Endothelin-1 (ET-1), and 2 G-protein coupled receptors, the ET receptor A (ETAR) and ET receptor B (ETBR). In the last decades it has been demonstrated that the ET axis is able to promote the development and progression of tumor cells in an autocrine and/or paracrine fashion. Accordingly, recent experimental and clinical data obtained in solid tumors have evidenced the possibility of interfering with ET receptors (ETRs) - via specific antagonists - for therapeutic purposes. On the basis of these premises, primary aim of this study was to assess whether the ET axis may have a protumorigenic role in MM, therefore becoming a therapeutic target. The experimental evidences we obtained demonstrated that MM cell lines, primary MM PCs and BM microenvironment cells express ET-1 transcript and release the corresponding protein. Interestingly, while ETAR was constitutively expressed by PCs from healthy donors, primary malignant PCs and MM cell lines, ETBR was detected only on malignant PCs of 54 of the 100 patients enrolled in the study and in 3/5 MM cell lines. Interestingly, B lymphocytes isolated from healthy donors BM or peripheral blood (PB) or from MM patients PB, did express ETAR but not ETBR. Based on the evidence that the expression of ETBR was strictly connected to the neoplastic transformation, we next demonstrated an altered methylation status of the ETBR promoter gene in malignant PCs from ETBR-expressing MM patients and MM cell lines. The possibility of interfering with, No, embargoed_20170902, Spina, C, Spina, C

Endothelin receptor antagonists are approved for pulmonary arterial hypertension. Development of selective ETA-receptor antagonists over mixed or dual receptor antagonists has depended on a range of receptor binding assays, second messenger assays and functional blood vessel assays. This study compared the 3 clinically-approved endothelin receptor antagonists in assays of human isolated pulmonary and radial arteries in vitro. METHODS: Human isolated pulmonary (i.d. 5.5mm) and human radial (i.d. 3.23mm) artery ring segments were mounted in organ baths for isometric force measurement. Single concentration-contraction curves to endothelin-1 were constructed in the absence or presence of bosentan (1-10µM), macitentan (0.03-0.3µM) or ambrisentan (0.1-1µM). RESULTS: All 3 endothelin antagonists caused competitive rightward shifts in the endothelin-1 concentration-response curves in both arteries. The Clark plot and analysis gave the following pKB values: bosentan, pulmonary artery 6.28±0.13 and radial artery 6.04±0.10; macitentan, pulmonary artery 8.02±0.13 and radial artery 7.49±0.08; and ambrisentan, pulmonary artery 7.38±0.13 and radial artery 6.96±0.10. CONCLUSIONS: Noting the maximum plasma levels attained from recommended oral doses of each antagonist in volunteers, the pKB findings here show that there would be significant antagonism of endothelin-1 contraction in the pulmonary and radial arteries at therapeutic plasma levels. This functional assay confirms in human tissue that much higher plasma concentrations of endothelin-1 receptor antagonists are required to be effective than those predicted from binding or other biochemical assays.

Endothelin 1 (ET-1), a potent vasoconstrictor, pro-mitogenic and pro-inflammatory peptide, may promote development of endothelial dysfunction and arterial remodeling. ET-1 can be formed through cleavage of big-ET-1 by endothelin-converting enzyme (ECE) or neutral endopeptidase (NEP). We investigated whether chronic treatment with the novel dual NEP/ECE inhibitor SOL1 improves functional and structural properties of resistance-sized arteries of 32-week-old male spontaneously hypertensive rats (SHR). SHR received a chronic 4-week treatment with SOL1, losartan or hydralazine. We then compared effects of inhibition of NO synthase (NOS) (100 mu M L-NAME), blockade of ETA-and ETB-receptors (10 mu M bosentan) and stimulation of the endothelium with 0.001-10 mu M acetylcholine (ACh) in isolated third-order mesenteric resistance arteries. Losartan and hydralazine significantly lowered blood pressure. Losartan decreased the media-to-lumen ratio of resistance arteries. L-NAME (1) increased arterial contractile responses to K+ (5.9-40 mM) in the losartan, SOL1 and vehicle group and (2) increased the sensitivity to phenylephrine (PHE; 0.16-20 mu M) in the SOL1 group but not in the losartan, hydralazine and vehicle group. Relaxing responses to ACh in the absence or presence of L-NAME during contractions induced by either 10 mu M PHE or 40 mM K+ were not altered by any in vivo treatment. Acute treatment with bosentan did, however, significantly improve maximal relaxing responses involving endothelium-derived nitric oxide and -hyperpolarizing factors in the SOL1 group but not in the losartan, hydralazine or vehicle group. Thus, chronic inhibition of NEP/ECE improved basal endothelial function but did not alter blood pressure, resistance artery structure and stimulated endothelium-dependent relaxing responses in 32-week-old SHR.

Multiple Myeloma (MM) is a monoclonal tumor of bone marrow (BM) plasma cell (PC), usually associated with a number of disease manifestations, including skeletal damage, anemia and immunosuppression. Despite recent therapeutic advances and an increased patient life expectancy, MM still remains an incurable malignancy. MM PC is characterized by a strong BM niche dependence, acquiring an autonomous capacity of growth only in the latter stages of disease. The endothelin (ET) axis is mainly composed of Endothelin-1 (ET-1), and 2 G-protein coupled receptors, the ET receptor A (ETAR) and ET receptor B (ETBR). In the last decades it has been demonstrated that the ET axis is able to promote the development and progression of tumor cells in an autocrine and/or paracrine fashion. Accordingly, recent experimental and clinical data obtained in solid tumors have evidenced the possibility of interfering with ET receptors (ETRs) - via specific antagonists - for therapeutic purposes. On the basis of these premises, primary aim of this study was to assess whether the ET axis may have a protumorigenic role in MM, therefore becoming a therapeutic target. The experimental evidences we obtained demonstrated that MM cell lines, primary MM PCs and BM microenvironment cells express ET-1 transcript and release the corresponding protein. Interestingly, while ETAR was constitutively expressed by PCs from healthy donors, primary malignant PCs and MM cell lines, ETBR was detected only on malignant PCs of 54 of the 100 patients enrolled in the study and in 3/5 MM cell lines. Interestingly, B lymphocytes isolated from healthy donors BM or peripheral blood (PB) or from MM patients PB, did express ETAR but not ETBR. Based on the evidence that the expression of ETBR was strictly connected to the neoplastic transformation, we next demonstrated an altered methylation status of the ETBR promoter gene in malignant PCs from ETBR-expressing MM patients and MM cell lines. The possibility of interfering with

Long-term repeated-dose toxicity is mainly assessed in animals despite poor concordance of animal data with human toxicity. Nowadays advanced human in vitro systems, eg, metabolically competent HepaRG cells, are used for toxicity screening. Extrapolation of in vitro toxicity to in vivo effects is possible by reverse dosimetry using pharmacokinetic modeling. We assessed long-term repeated-dose toxicity of bosentan and valproic acid (VPA) in HepaRG cells under serum-free conditions. Upon 28-day exposure, the EC50 values for bosentan and VPA decreased by 21- and 33-fold, respectively. Using EC(10) as lowest threshold of toxicity in vitro, we estimated the oral equivalent doses for both test compounds using a simplified pharmacokinetic model for the extrapolation of in vitro toxicity to in vivo effect. The model predicts that bosentan is safe at the considered dose under the assumed conditions upon 4 weeks exposure. For VPA, hepatotoxicity is predicted for 4% and 47% of the virtual population at the maximum recommended daily dose after 3 and 4 weeks of exposure, respectively. We also investigated the changes in the central carbon metabolism of HepaRG cells exposed to orally bioavailable concentrations of both drugs. These concentrations are below the 28-day EC(10) and induce significant changes especially in glucose metabolism and urea production. These metabolic changes may have a pronounced impact in susceptible patients such as those with compromised liver function and urea cycle deficiency leading to idiosyncratic toxicity. We show that the combination of modeling based on in vitro repeated-dose data and metabolic changes allows the prediction of human relevant in vivo toxicity with mechanistic insights.

Inhaled nitric oxide (iNO) is approved for use in persistent pulmonary hypertension of the newborn (PPHN) but does not lead to sustained improvement in oxygenation in one-third of patients with PPHN. Inhaled NO is less effective in the management of PPHN secondary to congenital diaphragmatic hernia (CDH), extreme prematurity, and bronchopulmonary dysplasia (BPD). Intravenous pulmonary vasodilators such as prostacyclin, alprostadil, sildenafil, and milrinone have been successfully used in PPHN resistant to iNO. Oral pulmonary vasodilators such as endothelin receptor antagonist bosentan and phosphodiesterase-5 inhibitors such as sildenafil and tadalafil are used both during acute and chronic phases of PPHN. In the absence of infection, glucocorticoids may also be effective in PPHN. Many of these pharmacologic agents are not approved for use in PPHN and our knowledge is based on case reports and small trials. Large multicenter randomized controlled trials with long-term follow-up are required to evaluate alternate pharmacologic strategies in PPHN.

The exact pathogenesis of multiple sclerosis (MS) is incompletely understood. Although auto-immune responses have an important role in the development of hallmark focal demyelinating lesions, the underlying mechanism of axonal degeneration, the other key player in MS pathology and main determinant of long-term disability, remains unclear and corresponds poorly with inflammatory disease activity. Perfusion-weighted imaging studies have demonstrated that there is a widespread cerebral hypoperfusion in patients with MS, which is present from the early beginning to more advanced disease stages. This reduced cerebral blood flow (CBF) does not seems to be secondary to loss of axonal integrity with decreased metabolic demands but appears to be mediated by elevated levels of the potent vasospastic peptide endothelin-1 in the cerebral circulation. Evidence is evolving that cerebral hypoperfusion in MS is associated with chronic hypoxia, focal lesion formation, diffuse axonal degeneration, cognitive dysfunction, and fatigue. Restoring CBF may therefore emerge as a new therapeutic target in MS.

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 < 0.05). Reduced serum uric acid correlated with increased 6MWD (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. © 2014 International Society for Heart and Lung Transplantation. All rights reserved., SCOPUS: ar.j, info:eu-repo/semantics/published

PurposePlastic bronchitis is the occlusion of the major bronchial airways by a firm, gelatinous mucoid cast. It is a rare condition, which while classically described in asthma and sickle cell disease has greater mortality in patients with congenital heart disease. The management of this disease is obscure given the lack of clinical data regarding treatment therapies.MethodsWe describe a case of an 11-year-old female status after Fontan surgery who presented with respiratory distress secondary to atelectasis of the right lung.ResultsA bronchoscopy was performed demonstrating an obstructing bronchial cast with successful extraction. The plastic bronchitis continued to recur and she was placed on multiple inhaled mucolytics as well as inhaled tissue plasminogen activator with temporary resolution. Further evaluation of the etiology of her casts revealed that she had elevated pulmonary arterial pressures. Repeated bronchoscopic removal of the casts was utilized as well as continuation of the aggressive airway clearance. Ultimately fenestration of her Fontan was performed along with treatment of pulmonary vasodilators sildenafil and bosentan. Although there was improvement of the cast formation, her airway clearance could only be weaned to four times a day therapy with which she was discharged home after a 3-month hospitalization. She continues to remain on this therapy and has not required hospitalization since the initial incident over 1 year ago.ConclusionsPlastic bronchitis in a patient with Fontan physiology presents a treatment dilemma that may require comprehensive therapy in severe cases such as described.

Background/Purpose: We sought to determine predictors of mortality in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). Method(s): This was a retrospective cohort study of patients with CTD-PAH recruited from six tertiary hospitals. In addition to data prospectively collected as part of the Australian Scleroderma Cohort Study, physician records were reviewed. PAH was defined on right heart catheterization. All patients had systemic sclerosis (SSc) or another underlying CTD. Records were censored at 31/12/09. Survival was determined using Kaplan-Meier estimates. Univariate and multivariable predictors of survival were determined using log-rank / Wilcoxon tests, and proportional hazards regression modelling. Result(s): Amongst 117 patients (105 female) there were 32 deaths. Mean age at PAH diagnosis was 61.5 +/- 11.4 years. SSc was the most common underlying CTD, accounting for 104 patients (88.9%). Forty-eight patients (41.0%) had coexistent interstitial lung disease (ILD). At baseline, mean six-minute walk distance was 325 +/- 127 m and 88 patients (75.2%) were in WHO functional class III. Average duration of follow-up from PAH diagnosis was 2.6 +/- 1.8 years. Seventy patients (59.8%) received monotherapy, 12 (10.3%) sequential monotherapy and 34 (29.0%) combination pulmonary vasodilator therapy. Bosentan was the most commonly prescribed medication, used in 102 patients (87.2%). Sildenafil was the next most common, followed by inhaled iloprost and sitaxentan. One-, two- and three-year survival was 94%, 89% and 73%, respectively (see Figure 1). On univariate analysis, predictors of mortality were WHO functional class IV at baseline, male sex, ILD, right ventricular dysfunction, pericardial effusion, absence of warfarin therapy, absence of combination therapy and higher mean right atrial pressure (mRAP) at PAH diagnosis. On multiple regression analysis, WHO functional class IV at baseline, higher mRAP at PAH diagnosis, coexistent ILD and

PURPOSE OF REVIEW: Since the late 1990 s, when a more uniform definition of idiopathic pulmonary fibrosis (IPF) was proposed, more than 3000 patients have been enrolled in clinical studies exploring novel therapies. Some of the most relevant trials have been published only recently. RECENT FINDINGS: This review describes and comments on the randomized clinical trials in IPF published within the past 18 months, with emphasis on the studies evaluating pirfenidone, which at present is the only drug approved for IPF (at least in Europe and Japan), and bosentan. This latter represents the largest single trial performed in IPF so far. SUMMARY: Despite multiple clinical trials, there is no strong, definitive evidence in favor of any agent to treat IPF. On the other hand, the placebo arms of these large trials have provided us with important critical information on the natural history of this disease. Clinical heterogeneity represents a critical issue to be taken into account in designing future clinical trials. The limited effectiveness of current treatment regimes has fuelled the search for a variety of new therapeutic approaches.

Background: Pulmonary arterial hypertension (PAH) affects up to 12% of patients with systemic sclerosis (SSc). Although new therapy has improved survival, PAH continues to be associated with high mortality. Objective(s): To determine the prevalence of PAH in an Australian cohort of patients with SSc and to describe their clinical characteristics. Method(s): Since 2007, the Australian Scleroderma Interest Group (ASIG) has coordinated a nation-wide screening program for cardiopulmonary complications in patients with SSc and mixed connective tissue disease (MCTD). 794 patients have been enrolled from 13 participating centres. Patients undergo annual clinical assessment and investigation with echocardiogram and lung function tests. Abnormalities in these tests trigger further investigations according to a screen-ing algorithm. These additional investigations include the 6-minute walk test (6MWT), CT chest and right heart catheter (RHC). Clinical and laboratory data from the visits are recorded and tracked in a Web-based database. Result(s): To date 101 of the 794 (12.7%) patients have been found to have PAH on RHC. 87% of patient with PAH are female. 65% have limited scleroderma (lcSSc), 25% have diffuse disease (dcSSc) and 7% have MCTD. Mean+/-SD disease duration at the time of diagnosis of PAH in those with dcSSc and lcSSc was 11.9+/-11.1 and 15.7+/-13.2 years, respectively. RHC-defined PAH was present at rest in 84% and on exercise in 16% of patients. Mean pulmonary artery pressure at diagnosis of PAH was 34.1 mmHg (min-max, 26-68). Mean pulmonary vascular resistance at diagnosis of PAH was 4.1 Woods units (1.2-13). Mean 6MWT distance at diagnosis of PAH was 357 meters (50-595). In 11 patients PAH was associated with significant interstitial lung disease, with an FVC < 75% predicted. At time of diagnosis, 5.4% were in WHO functional class 1,17.9% in class II, 71.4% in class HI and 5.4% in class IV. 95 of 101 (94.1%) have received specific PAH therapy. 93% have been t

Aim: To determine predictors of mortality in a cohort of patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH). Method(s): This was a retrospective cohort study of patients with CTD-PAH recruited from six tertiary hospitals. Patients were identified using the Australian Scleroderma Screening Program database and in addition to data prospectively collected, physician records were reviewed. PAH was defined on right heart catheter findings. All patients had systemic sclerosis (SSc) or another underlying CTD. Records were censored at 31/12/09. Survival was determined using Kaplan-Meier estimates and univariate predictors of survival were determined using the Log-rank and Wilcoxon tests. Result(s): Of the 112 patients, 101 (90.2%) were female. Mean age at PAH diagnosis was 61.0 + 11.4 years. SSc was the most common underlying CTD, accounting for 101 patients (90.2%). Forty-three patients (38.4%) had coexisting interstitial lung disease (ILD). At baseline, mean six minute walk distance was 323 + 131 m and 83 patients (94.6%) were in WHO functional class III. Average duration of follow-up from PAH diagnosis was 2.7 + 1.9 years. Sixty-six patients (58.9%) received monotherapy, 13 patients (11.6%) sequential monotherapy and 32 patients (28.6%) combination therapy. Bosentan was the most commonly prescribed medication, used in 99 patients (88.4%). Sildenafil was the next most common, followed by inhaled iloprost and sitaxentan. One-, two- and three-year survival was 93.4%, 87.9% and 72.0% respectively. On univariate analysis, predictors of mortality were higher baseline WHO functional class, male sex, ILD, right ventricular dysfunction, pericardial effusion, absence of warfarin therapy and higher right atrial pressure at PAH diagnosis. Conclusion(s): In this study, three-year survival was 72%; this is better than in historical series from the pre-treatment era and is comparable with what is described internationally. Predictors of mortali

SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND: Pulmonary arterial hypertension (PAH) is a devastating disease, which leads to right heart failure and premature death. Pulmonary arterial hypertension can be classified into two categories: 1) sporadic primary pulmonary hypertension (PPH) or familial PPH and 2) PAH secondary to collagen vascular diseases, congenital systemic to pulmonary shunts, portal hypertension, HIV infection, drugs or toxins, and persistent pulmonary hypertension of the newborn. They have identical pathologic features, a similar clinical course. Endothelin receptor antagonists (ERAs) are a class of potent vasodilators, which could specifically dilate the pulmonary arterial system. OBJECTIVE(S): To evaluate the efficacy of endothelin receptor antagonists in pulmonary arterial hypertension. SEARCH STRATEGY: A search was carried out using the CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE, and the reference section of retrieved articles. Searches are current as of August 2004. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-randomised controlled trials involving patients with pulmonary arterial hypertension (PAH) were selected by two reviewers. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected studies; assessed study quality; and extracted data. We analysed outcomes as continuous and dichotomous data. MAIN RESULTS: We identified three RCTs of short duration (12-16 weeks), recruiting a total of 423 participants. Two studies compared a non-selective ERA (bosentan) with placebo and one compared a selective ERA (sitaxsentan) with placebo. Over a 12-16 week period ERAs improved exercise capacity, improve Borg dyspnoea score, some measures of cardiopulmonary haemodynamics (pulmonary artery pressure, pulmonary vascular resistance, and cardiac index) in symptomatic patients with PAH. The most severe side effect, hepatic toxicity, was not common. AUTHORS' CONCLUSION(S): ERAs in conjunction with conventional therapy over 16 weeks can

Background. The relative roles of endothelin (ET)-1 and angiotensin (ANG) II in post-ischaemic acute renal failure (ARF) have not been fully established so far. With the aim of contributing to this goal, we assessed in this study the effect of ANG II and ET-1 blockade on the course of post-ischaemic-ARF. Methods. Anaesthetized Wistar rats received i.v. either bosentan (a dual ET receptor antagonist; 10 mg/kg body weight) or losartan [ANG II type 1 (AT(1)) receptor antagonist; 5 or 10 mg/kg body weight] or both, 20 min before, during and 20 min after ischaemia. Rats in the control group received the vehicle via the same route. Survival and renal function were monitored up to 8 days after the ischaemic challenge, while haemodynamic parameters were measured 24 h after ARF. Results. Our results demonstrate that bosentan treatment has a more beneficial effect on experimental ARF than losartan. The survival rate was remarkably higher in bosentan-treated rats than in both rat groups treated with losartan. In the ARF group treated with bosentan, renal blood flow (RBF) was increased by 129% in comparison with the untreated ARF group, whereas in the losartan-treated ARF groups, RBF was only similar to35 or 38% higher than in control ARF rats. The glomerular filtration rate was markedly higher in bosentan-treated rats than in all other ARF groups on the first and second day after ischaemia. Tubular cell injury was less severe in bosentan-treated rats than in the control ARF rats, but in losartan-treated groups it was similar to that in the ARF group. Concurrent blockade of both ET and AT(1) receptors did not improve ARF because this treatment induced a marked decrease in blood pressure. Conclusions. These results suggest that ET-1 blockade is more efficient in improving the early course of post-ischaemic renal injury than ANG II inhibition, and that blockade of ET-1 might be effective in prophylaxis of ischaemic ARF.

The main goal of this study was to examine the efficacy of endothelin (ET) receptor blockade in the course of experimental postischaemic acute renal failure (ARF). Experiments were performed on male adult Wistar rats. The right kidney was removed before renal ischaemia (by clamping the left renal artery for 45 minutes). The experimental groups received either bosentan (ETA/ETB-receptor antagonist; 10mg/kg/b.m) or vehicle (saline) in the femoral vein 20 minutes before, during and 20 minutes after ischaemia. All parameters were measured 24 hours after reperfusion. The obtained results clearly demonstrate that bosentan yields beneficial effect on ARF. Bosentan improves both renal haemodynamic and functional parameters after ARF, while lesions of tubular epithelial cells, the principal targets of injury in ARF are less serious in bosentan-treated rats than in the control ARF rats. This strongly suggests that endothelins have an important role in the development of ischaemia/'reperfusion injury and contributes to the promotion of bosentan in future clinical practice., Uticaji blokade receptora endotelinskih peptida na tok postishemične eksperimentalne akutne bubrežne insuficijencije (ABI), predstavljali su glavni cilj naših istraživanja. Eksperimenti su izvođeni na odraslim pacovima Wistar soja. Urađena je netrektomija desnog bubrega, a leva bubrežna arterija je klemovana u trajanju od 45 minuta. Eksperimentalne grupe su prekofemoralne vene primale Hi bpsentan (antagonist ETA/ETB-receptora) Hi fiziološki rastvor, kontinuirano, 20 minuta pre, tokom i 20 minuta posle perioda ishemije. Svi parametri su mereni 24 časa nakon perioda ishemije. Dobijeni rezultati jasno pokazuju da bozentan iskazuje povoljne uticaje na tok ABI. Bozentan poboljšava bubrežne hemodinamske i funkcionalne parametre, a lezije epitelnih ćelija tubula (glavnih mesta oštećenja u ABI), su manje izražene kod pacova tretiranih bosentanom, negp kod kontrolnih životinja sa ABI. Sve to navodi na zaključak da endotelini imaju uticaja u razvoju ishemično/reperfuzionih oštećenja u ABI i da bosentan poseduje potencijal za primenu u kliničkoj praksi.