PRIME score for prediction of permanent pacemaker implantation after transcatheter aortic valve replacement.

OBJECTIVES: We sought to produce a simple scoring system that can be applied at clinical visits before transcatheter aortic valve replacement (TAVR) to stratify the risk of permanent pacemaker (PPM) after the procedure. BACKGROUND: Atrioventricular block is a known complication of TAVR. Current models for predicting the risk of PPM after TAVR are not designed to be applied clinically to assist with preprocedural planning. METHODS: Patients undergoing TAVR at the University of Colorado were split into a training cohort for the development of a predictive model, and a testing cohort for model validation. Stepwise and binary logistic regressions were performed on the training cohort to produce a predictive model. Beta coefficients from the binary logistic regression were used to create a simple scoring system for predicting the need for PPM implantation. Scores were then applied to the validation cohort to assess predictive accuracy. RESULTS: Patients undergoing TAVR from 2013 to 2019 were analyzed: with 483 included in the training cohort and 123 included in the validation cohort. The need for a pacemaker was associated with five preprocedure variables in the training cohort: PR interval > 200 ms, Right bundle branch block, valve-In-valve procedure, prior Myocardial infarction, and self-Expandable valve. The PRIME score was developed using these clinical features, and was highly accurate for predicting PPM in both the training and model validation cohorts (area under the curve 0.804 and 0.830 in the model training and validation cohorts, respectively). CONCLUSIONS: The PRIME score is a simple and accurate preprocedural tool for predicting the need for PPM implantation after TAVR.

Discovery and initial optimization of alkoxyanthranilic acid derivatives as inhibitors of HCV NS5B polymerase.

Alkoxyanthranilic acid derivatives have been identified to inhibit HCV NS5B polymerase, binding in an allosteric site located at the convergence of the palm and thumb regions. Information from co-crystal structures guided the structural design strategy. Ultimately, two independent structural modifications led to a similar shift in binding mode that when combined led to a synergistic improvement in potency and the identification of inhibitors with sub-micromolar HCV NS5B binding potency.

Incidence of Cancer Treatment Induced Arrhythmia Associated with Immune Checkpoint Inhibitors.

BACKGROUND: Cancer treatmentinduced arrhythmia (CTIA) is a well-recognized form of cardiotoxicity associated with chemotherapy. Immune checkpoint inhibitors (ICI) have been associated with important forms of cardiotoxicity, including myocarditis. However, the incidence of CTIA associated with ICI has not been well characterized. METHODS: We reviewed all patients treated with ICIs at our institution from Jan. 2010 to Oct. 2015. CTIA was defined as a new diagnosis of clinically relevant arrhythmia within 6 months after ICI initiation. RESULTS: During the study period, 268 patients were treated with immune checkpoint inhibitors, of whom 190 received monotherapy with ipilimumab (n=114), nivolumab (n=52) or pembrolizumab (n=24) and 78 received combination therapy: ipilimumab & nivolumab (n=37), ipilimumab & pembrolizumab (n=39) and nivolumab & pembrolizumab (n=2). Four patients (1.5%) developed CTIA. Of these, 3 patients developed a new diagnosis of atrial fibrillation (AF), one of whom required cardioversion. In 2 cases of new-onset AF, significant provoking factors were present in addition to ICI therapy including thyrotoxicosis in one and metabolic disarray in another. Six patients (2.2%) with a pre-existing diagnosis of paroxysmal AF experienced episodes within 6 months of initiating ICI therapy. None of the arrhythmic events were associated with known or suspected myocarditis. CONCLUSIONS: The incidence of arrhythmic complications associated with immune checkpoint inhibitors appears to be very low (~1.5%). Patients with a pre-existing diagnosis of AF may be at-risk of recurrence during ICI treatment and should be monitored accordingly. These suggest that from an arrhythmia perspective, ICIs appear to be very safe and well-tolerated.

Incidence of Cancer Treatment-Induced Arrhythmia Associated With Novel Targeted Chemotherapeutic Agents.

Background The incidence of cancer treatment-induced arrhythmia ( CTIA ) associated with novel, targeted chemotherapeutic agents ( TCA s) has not been well described. Methods and Results We identified all patients treated at our institution from January 2010 to December 2015 with selected TCA s. We defined CTIA as any new arrhythmia diagnosis code within 6 months after treatment initiation. As a comparison, we also identified patients treated with anthracycline chemotherapy during the same period. We identified 5026 patients, of whom 2951 (58.7%) received TCA s and 2075 (41.3%) received anthracycline chemotherapy. In the overall cohort, 601 patients (12.0%) developed CTIA . Patients with CTIA were significantly older and more likely to have hypertension, diabetes mellitus, congestive heart failure, coronary disease, and sleep apnea. The incidence of CTIA at 6 months was significantly lower in the TCA group (9.3% versus 15.8%; P<0.001). In multivariate analysis, a history of hypertension (hazard ratio, 1.63; 95% confidence interval, 1.34-1.98), congestive heart failure (hazard ratio, 2.12; 95% confidence interval, 1.78-2.68), and male sex (hazard ratio, 1.25; 95% confidence interval, 1.06-1.47) were associated with a significantly increased risk of CTIA , whereas treatment with TCA s, compared with anthracycline chemotherapy, was associated with a significantly lower risk (hazard ratio, 0.60; 95% confidence interval, 0.51-0.71). Conclusions Compared with anthracyclines, treatment with TCAs was associated with an ≈40% reduced risk of new-onset arrhythmia diagnoses during the first 6 months of treatment.

Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies.

The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.

Discovery and preclinical characterization of the cyclopropylindolobenzazepine BMS-791325, a potent allosteric inhibitor of the hepatitis C virus NS5B polymerase.

Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.

Low catalyst loadings in olefin metathesis: synthesis of nitrogen heterocycles by ring-closing metathesis.

A series of ruthenium catalysts have been screened under ring-closing metathesis (RCM) conditions to produce five-, six-, and seven-membered carbamate-protected cyclic amines. Many of these catalysts demonstrated excellent RCM activity and yields with as low as 500 ppm catalyst loadings. RCM of the five-membered carbamate series could be run neat, the six-membered carbamate series could be run at 1.0 M, and the seven-membered carbamate series worked best at 0.2-0.05 M.

Total synthesis of ingenol.

A total synthesis of the biologically important diterpene ingenol has been completed. Ring-closing olefin metathesis was used to construct the strained "inside-outside" tetracyclic skeleton, and a series of diastereoselective reactions were employed to complete the synthesis. Another naturally occurring ingenane, 20-deoxyingenol, has also been prepared.