Endothelin receptor antagonists for the treatment of pulmonary artery hypertension

AbstractAimsThe demonstration that endothelin production is upregulated in pulmonary artery hypertension (PAH) served as the rationale for developing endothelin-receptor antagonists (ERAs) as a treatment for PAH. This article reviews the primary studies demonstrating efficacy of ERAs in PAH.Main methodsMulticenter, placebo-controlled trials and open-label extension studies.Key findingsTwo orally active ERAs are currently approved for the treatment of PAH — the dual receptor antagonist bosentan, and the more selective ETA receptor antagonist ambrisentan-based on multicenter randomized clinical trials demonstrating efficacy and safety. Long-term experience with both agents supports maintenance of therapeutic effects in most patients. Adverse effects, including altered liver function and edema may occur and require careful monitoring.SignificanceDespite failure to demonstrate efficacy of ERAs in other cardiopulmonary conditions, ERAs have a major role in the treatment algorithm for PAH

Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

In the early 1990s, within three years of cloning of endothelin receptors, orally active endothelin receptor antagonists (ERAs) were tested in humans and the first clinical trial of ERA therapy in humans was published in 1995. ERAs were subsequently tested in clinical trials involving heart failure, pulmonary arterial hypertension, resistant arterial hypertension, stroke/subarachnoid hemorrhage and various forms of cancer. The results of most of these trials – except those for pulmonary arterial hypertension and scleroderma-related digital ulcers – were either negative or neutral. Problems with study design, patient selection, drug toxicity, and drug dosing have been used to explain or excuse failures. Currently, a number of pharmaceutical companies who had developed ERAs as drug candidates have discontinued clinical trials or further drug development. Given the problems with using ERAs in clinical medicine, at the Twelfth International Conference on Endothelin in Cambridge, UK, a panel discussion was held by clinicians actively involved in clinical development of ERA therapy in renal disease, systemic and pulmonary arterial hypertension, heart failure, and cancer. This article provides summaries from the panel discussion as well as personal perspectives of the panelists on how to proceed with further clinical testing of ERAs and guidance for researchers and decision makers in clinical drug development on where future research efforts might best be focused

Do selected drugs increase the risk of lupus? A matched case-control study

WHAT IS ALREADY KNOWN ON THIS SUBJECT • Numerous previous case reports have suggested that lupus can be induced by a range of prescription medications.• Analytical studies quantifying risk of drug-induced lupus are lacking. WHAT THIS STUDY ADDS • This was the first large study to quantify risk of lupus associated with carbamazepine, hydralazine, and other prescription medicines suspected of inducing the disease.• We confirmed some, but not all, associations that have been hypothesized in case reports.• This study provides evidence that increased risks may be causal given the lack of an increased risk observed with deliberately selected ‘comparison’ drugs.To investigate the association between risk of lupus and exposure to selected drugs implicated in risk of lupus in a number of case reports.In this matched nested case-control study we utilized primary care data from the UK General Practice Research Database recorded between 1987 and 2001. Cases with at least one medical code for systemic lupus erythematosus or drug-induced lupus in their computerized records were matched to controls without a medical code for lupus or any other autoimmune disorder. Using conditional logistic regression we computed odds ratios (OR) and 95% confidence intervals (CI) for risk of lupus associated with exposure to selected drugs.There were 875 incident cases, of which 12% ( n = 107) had evidence of a prescription for one or more of the suspected drugs, and 3632 matched controls. For some drugs, prescriptions were too uncommon to be able to estimate associated risk of lupus. Despite small numbers of exposed patients and low statistical precision we observed an increased risk of lupus for hydralazine (OR = 6.62, 95% CI 1.03, 42.74), minocycline (OR = 4.23, 95% CI 2.65, 6.75) and carbamazepine (OR = 1.88, 95% CI 1.09, 3.22). There was some indication that the effect of carbamazepine was restricted to women ( P for interaction by gender = 0.047).This study shows that even those drugs suggested by case reports as causing lupus cannot all be clearly shown to be associated, even in a very large population-based database. Our findings support causal relationships for carbamazepine, minocycline and possibly hydralazine. Overall, drugs do not seem to be a major cause of lupus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79216/1/j.1365-2125.2010.03733.x.pd

Inhaled treprostinil: a therapeutic review

Pulmonary arterial hypertension (PAH) is a life-threatening disease which, if untreated, leads to right ventricular failure and often death. Several effective therapies are now available for PAH, including endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogs. The prostacyclin analog treprostinil has proven efficacious when delivered by subcutaneous or intravenous infusion, and most recently by inhalation. Inhaled treprostinil has been shown to be 64%–72% bioavailable in healthy volunteers. Pilot clinical studies have elucidated the acute hemodynamic effects and relative pulmonary selectivity of this agent, as well as established target dosing in PAH and nonoperable chronic thromboembolic PAH. Likewise, chronically administered inhaled treprostinil resulted in clinical and hemodynamic improvement. Both pilot studies confirmed a satisfactory safety profile in patients with PAH. The pivotal Phase III trial, TRIUMPH-I, demonstrated the efficacy and safety of inhaled treprostinil (target dose of 54 μg four times daily) in PAH patients added to background therapies of bosentan or sildenafil, as assessed by improvements in the primary endpoint, peak six-minute walk distance (median placebo-corrected treatment effect of 20 m), as well as select secondary endpoints. Inhaled treprostinil is approved by the US Food and Drug Administration for patients with World Health Organization Group I PAH to improve exercise ability. Studies establishing effectiveness included predominately patients with New York Heart Association functional class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%)

Cooperation between MEF2 and PPARγ in human intestinal β,β-carotene 15,15'-monooxygenase gene expression

BACKGROUND: Vitamin A and its derivatives, the retinoids, are essential for normal embryonic development and maintenance of cell differentiation. β, β-carotene 15,15'-monooxygenase 1 (BCMO1) catalyzes the central cleavage of β-carotene to all-trans retinal and is the key enzyme in the intestinal metabolism of carotenes to vitamin A. However, human and various rodent species show markedly different efficiencies in intestinal BCMO1-mediated carotene to retinoid conversion. The aim of this study is to identify potentially human-specific regulatory control mechanisms of BCMO1 gene expression. RESULTS: We identified and functionally characterized the human BCMO1 promoter sequence and determined the transcriptional regulation of the BCMO1 gene in a BCMO1 expressing human intestinal cell line, TC-7. Several functional transcription factor-binding sites were identified in the human promoter that are absent in the mouse BCMO1 promoter. We demonstrate that the proximal promoter sequence, nt -190 to +35, confers basal transcriptional activity of the human BCMO1 gene. Site-directed mutagenesis of the myocyte enhancer factor 2 (MEF2) and peroxisome proliferator-activated receptor (PPAR) binding elements resulted in decreased basal promoter activity. Mutation of both promoter elements abrogated the expression of intestinal cell BCMO1. Electrophoretic mobility shift and supershift assays and transcription factor co-expression in TC-7 cells showed MEF2C and PPARγ bind to their respective DNA elements and synergistically transactivate BCMO1 expression. CONCLUSION: We demonstrate that human intestinal cell BCMO1 expression is dependent on the functional cooperation between PPARγ and MEF2 isoforms. The findings suggest that the interaction between MEF2 and PPAR factors may provide a molecular basis for interspecies differences in the transcriptional regulation of the BCMO1 gene

Clinical trials and basic research: defining mechanisms and improving treatment in connective tissue disease

Despite advances in elucidating the pathogenic factors responsible for its development, systemic sclerosis remains complex and poorly understood, and treatment options are limited. Multidisciplinary collaborative efforts are needed to better characterize clinical and prognostic parameters and to design and implement large-scale clinical trials in well defined populations with therapies that target potential disease modulators

Systemic sclerosis and related connective tissue diseases: present and future

Greece, to discuss systemic sclerosis (SSc) and related connective tissue diseases (CTDs). SSc is a clinically heterogeneous and complex disease that is characterized by vascular dysfunction, vascular and extravascular fibrosis, and characteristic immune derangements, and for which few treatment options are available. The aims of the CTD International Scientific Advisory Board were threefold: to define the role of local mediators in CTDs, in particular to identify the nature of the initial insult in CTDs and to consider the role of genetic perturbations in CTDs; to translate what has been learned from clinical trials into clinical practice and to evaluate current treatment options for CTDs and their complications; and to address future directions for the management of CTDs and associated rare diseases, based on the biologic mechanisms elucidated. This supplemen

A survey of obstetric complications and pregnancy outcomes in paediatric and nonpaediatric anaesthesiologists

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73884/1/j.1460-9592.2003.01079.x.pd