ABSTRACT
BACKGROUND: Initial combination therapy with an endothelin receptor antagonist (ERA) and riociguat in pulmonary arterial hypertension (PAH) has limited supporting data. METHODS: We performed a prospective, single-arm, open-label trial of riociguat, and ambrisentan for incident PAH patients in functional class III. The primary endpoint was pulmonary vascular resistance (PVR) at 4-months. RESULTS: Twenty patients (59 ± 13 years old, 85% female) enrolled and 1 died before their 4-month follow-up. Fifteen patients completed a 4-month and 13 completed the 12-month follow-up. At 4-months PVR decreased 54% with an absolute change of -5.8 Wood units (95% CI -4.0; -7.5, p < 0.001). Other hemodynamic variables and risk scores also improved. Six patients discontinued riociguat and 8 discontinued ambrisentan, with 5 (25%) discontinuing both. CONCLUSIONS: These results do not support the routine use of riociguat plus ambrisentan in initial regimens. Future studies are needed to compare this strategy with phosphodiesterase-5 inhibitors and an ERA with respect to tolerability and long-term outcomes.
Subject(s)
Hypertension, Pulmonary , Pulmonary Arterial Hypertension , Aged , Antihypertensive Agents/therapeutic use , Endothelin Receptor Antagonists/therapeutic use , Familial Primary Pulmonary Hypertension/drug therapy , Female , Humans , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/drug therapy , Male , Middle Aged , Phenylpropionates , Prospective Studies , Pyrazoles , Pyridazines , Pyrimidines , Treatment OutcomeABSTRACT
A 73-year-old woman with chronic myeloid leukemia developed severe pulmonary arterial hypertension (PAH) and pleural effusions after treatment with dasatinib. During workup, partial anomalous pulmonary venous connection and a sinus venosus atrial septal defect were found; these anomalies may have predisposed her to developing this rare and life-threatening condition. Fortunately, her PAH was completely reversible by discontinuation of dasatinib. This case highlights dasatinib's ability to cause PAH in patients predisposed to pulmonary vascular disease.
Subject(s)
Dasatinib/adverse effects , Pulmonary Arterial Hypertension/chemically induced , Pulmonary Wedge Pressure/drug effects , Adult , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Dasatinib/therapeutic use , Female , Follow-Up Studies , Humans , Imaging, Three-Dimensional , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Magnetic Resonance Imaging, Cine , Pulmonary Arterial Hypertension/diagnosis , Pulmonary Arterial Hypertension/physiopathology , Pulmonary Wedge Pressure/physiology , Tomography, X-Ray ComputedABSTRACT
Hyperproduction of AmpC beta-lactamase (AmpC) is a formidable mechanism of resistance to penicillins and cephalosporins in Gram-negative bacteria such as Pseudomonas aeruginosa and Enterobacteriaceae. AmpC expression is regulated by the LysR-type transcriptional regulator AmpR. ampR and ampC genes form a divergent operon with overlapping promoters to which AmpR binds and regulates the transcription of both genes. AmpR induces ampC by binding to one member of the family of 1,6-anhydro-N-acetylmuramyl peptides, which are cytosolic catabolites of peptidoglycan that accumulate during beta-lactam challenge. To gain structural insights into AmpR regulation, we determined the crystal structure of the effector binding domain (EBD) of AmpR from Citrobacter freundii up to 1.83 A resolution. The AmpR EBD is dimeric and each monomer comprises two subdomains that adopt alpha/beta Rossmann-like folds. Located between the monomer subdomains is a pocket that was found to bind the crystallization buffer molecule 2-(N-morpholino)ethanesulfonic acid. The pocket, together with a groove along the surface of subdomain I, forms a putative effector binding site into which a molecule of 1,6-anhydro-N-acetylmuramyl pentapeptide could be modeled. Amino acid substitutions at the base of the interdomain pocket either were found to render AmpR incapable of inducing ampC (Thr103Val, Ser221Ala and Tyr264Phe) or resulted in constitutive ampC expression (Gly102Glu). While the substitutions that prevented ampC induction did not alter the overall AmpR EBD structure, circular dichroism spectroscopy revealed that the nonconservative Gly102Glu mutation affected EBD secondary structure, confirming previous work suggesting that Gly102Glu induces a conformational change to result in constitutive AmpC production.
