Thelin (oral sitaxsentan) / Pfizer - LARVOL DELTA

Sitaxsentan in Proteinuric Chronic Kidney Disease (clinicaltrials.gov) - P2 | N=27 | Completed | Sponsor: University of Edinburgh | Unknown status ➔ Completed

Trial completion • Chronic Kidney Disease • Nephrology • Renal Disease

Comparative Effective Analysis of Treatment for Pulmonary Arterial Hypertension: An Individual Participant Data Network Meta-analysis (ATS 2023) - "We grouped the individual drugs based on treatment pathways: ambrisentan, bosentan, macitentan, and sitaxsentan were considered “endothelin pathway (EP)”, sildenafil, tadalafil, and riociguat were considered “nitric oxide pathway (NOP)”, while iloprost, selexipag, and treprostinil (subcutaneous, inhaled, and oral routes) were considered “prostacyclin pathway (PP)”. Drugs targeting the three traditional treatment pathways significantly improve outcomes in PAH. Combination therapy for the EP and NOP showed the most benefit on 6MWD and time to clinical worsening compared to monotherapy. Randomized clinical trials of treatment strategies are warranted to identify the most effective combination and sequence of treatments."

Retrospective data • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Pharmacological counseling in hepatotoxicity induced by macitentan and selexipag:  a case report. (PubMed, J Med Case Rep) - "A multidisciplinary approach based on clinical evaluation, as well as pharmacological counseling and evaluation of the patient's genetic profile, might be useful for identification of patients with a high chance of drug-induced liver injury, avoiding unnecessary risks in therapy selection and prescription."

Journal • Cardiovascular • Hepatology • Hypertension • Liver Failure • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • CYP2C9

Pharmacogenomics in Pulmonary Arterial Hypertension (clinicaltrials.gov) - P=N/A; N=0; Withdrawn; Sponsor: West Penn Allegheny Health System; N=1300 ➔ 0; Recruiting ➔ Withdrawn

Biomarker • Clinical • Enrollment change • Trial withdrawal • Hematological Disorders • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Unfavorable Reduction in the Ratio of Endothelin B to A Receptors in Experimental 5/6 Nephrectomy and Adenine Models of Chronic Renal Insufficiency. (PubMed, Int J Mol Sci) - "To conclude, unfavorable reduction in the ETB:ETA protein ratio was observed in two different models of CRI. Therefore, ETA blockade may be beneficial in a range of diseases that cause impaired kidney function."

Journal • Chronic Kidney Disease • Immunology • Inflammation • Nephrology • Renal Disease

Liver safety evaluation of endothelin receptor antagonists using HepatoPac : A single model impact assessment on hepatocellular health, function and bile acid disposition. (PubMed, J Appl Toxicol) - "Marketed (bosentan, ambrisentan) and discontinued (sitaxsentan, CI-1034) endothelin receptor antagonists were examined in the human micropatterned hepatocyte co-culture (MPCC) model HepatoPac . Differences across hepatocellular health (cellular adenosine triphosphate/glutathione content), function (urea production/albumin secretion) and taurocholic acid transport (biliary clearance/excretion index) were compared using amiodarone and ciclosporin A as positive controls...Although traditional animal testing provides adequate safety coverage for advancement of novel pharmaceuticals into clinical trials, supplemental assays employing human MPCCs may strengthen weight-of-evidence predictions for sensitive human populations. Proving the predictive value of this single impact assessment model in advance of clinical trial information for human liver injury risk is needed across more pharmaceuticals."

Clinical • Journal • Hepatology • Liver Failure

Application of a Novel Mass Spectral Data Acquisition Approach to Lipidomic Analysis of Liver Extracts from Sitaxentan-treated Liver-Humanized PXB Mice. (PubMed, J Proteome Res) - "This method of data generation provides both precursor and fragment ion information, at high specificity, allowing for greater accuracy of compound identification, without the need for spectral libraries. The value of the approach in simplifying and "de-cluttering" the spectra of co-eluting lipids is shown with examples from lipidomic profiles obtained in investigations of the composition of organic extracts of livers obtain from SCID and chimeric liver-humanized mice administered under various experimental conditions."

Journal • Preclinical

Drug Thelin deleted from the pipeline (Pfizer) - Thelin/ Pfizer

Corporate Pipeline Update

A systematic review of transition studies of pulmonary arterial hypertension specific medications. (PubMed) - Pulm Circ - "...Transitioning from parenteral epoprostenol to parenteral treprostinil appears to be safe and efficacious in patients who have less severe disease and more favorable hemodynamics...Currently, the only evidence in support of transitioning between oral PDE5 inhibitors is from sildenafil to tadalafil...In patients with liver abnormalities due to bosentan or sitaxentan, the transition to ambrisentan appears to be safe and can result in clinical improvement. Studies regarding PAH medication transitions are limited. Patients who have less severe disease, better functional status, and are on lower medications doses may be more successful at transitioning."

Journal • Biosimilar • Cardiovascular

Safety and Efficacy of Bosentan in Patients With Diastolic Heart Failure and Secondary Pulmonary Hypertension (clinicaltrials.gov) - P3; N=20; Completed; Sponsor: University Teaching Hospital Hall in Tirol; Trial primary completion date: Feb 2011 ->Jun 2014

Trial primary completion date • Acute Coronary Syndrome • Biosimilar • Heart Failure • Reperfusion Injury

Dichloroacetate (DCA) for the Treatment of Pulmonary Arterial Hypertension (clinicaltrials.gov) - P1; N=30; Completed; Sponsor: University of Alberta; N=40 -> 30

Enrollment change • Biosimilar • Immunology • Renal Cell Carcinoma

Simultaneous quantification of ambrisentan, macitentan and sitaxentan in human plasma by using UPLC-MS/MS. (PubMed, Biomed Chromatogr) - "The method was successfully validated according to FDA guidelines, to determine the concentration of macitentan, ambrisentan and sitaxentan in human plasma. This method is now being used for study samples and clinical patient samples."

Journal

Transfer and Vascular Effect of Endothelin Receptor Antagonists in the Human Placenta. (PubMed, Hypertension) - "Term placentas were dually perfused with the selective ETR (ET type A receptor) antagonists sitaxentan and ambrisentan or the nonselective ETR/ETR antagonist macitentan and subsequently exposed to ET-1 in the fetal circulation. Given its limited transfer, macitentan could be considered as potential preeclampsia therapy. Extending knowledge on placental transfer to placentas of preeclamptic pregnancies is required to determine whether ERAs might be applied safely in preeclampsia."

Journal

Number and brightness analysis to study spatio-temporal distribution of the angiotensin II AT and the endothelin-1 ET receptors: Influence of ligand binding. (PubMed, Biochim Biophys Acta Gen Subj) - "Our results showed that stably transfected angiotensin II AT receptors and transiently transfected endothelin 1 ET receptors, were found as monomeric, dimeric, and tetrameric receptor aggregates. Interestingly, the binding of antihypertensive agents like losartan and BQ123, earlier suggested to be inverse agonists, significantly increased the proportion of monomers and reduced the occurrence of dimers on the cell membrane; while the kown endothelin 1 ET antagonist sitaxentan did not influence the aggregation state of these receptors."

Journal

Endothelin Receptor Antagonism Improves Lipid Profiles and Lowers PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) in Patients With Chronic Kidney Disease. (PubMed, Hypertension) - P2; "Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ET receptor antagonist, sitaxentan, or long-acting nifedipine...Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00810732."

Clinical • Journal

Selective ETA versus dual ETA/B receptor blockade for the prevention of sunitinib-induced hypertension and albuminuria in WKY rats. (PubMed, Cardiovasc Res) - "Our results demonstrate that both selective ETA and dual ETA/B receptor antagonism prevents sunitinib-induced hypertension, while sunitinib-induced albuminuria was only prevented by selective ETA receptor antagonism. Additionally, our results uncover a role for prostacyclin in the development of these effects. In conclusion, selective ETA receptor antagonism is sufficient for the prevention of sunitinib-induced hypertension and renal injury."

Journal • Preclinical