Endogenous digitalis: pathophysiologic roles and therapeutic applications

Endogenous digitalis-like factors, also called cardiotonic steroids, have been thought for nearly half a century to have important roles in health and disease. The endogenous cardiotonic steroids ouabain and marinobufagenin have been identified in humans, and an effector mechanism has been delineated by which these hormones signal through the sodium/potassium-transporting ATPase. These findings have increased interest in this field substantially. Although cardiotonic steroids were first considered important in the regulation of renal sodium transport and arterial pressure, subsequent work has implicated these hormones in the control of cell growth, apoptosis and fibrosis, among other processes. This Review focuses on the role of endogenous cardiotonic steroids in the pathophysiology of essential hypertension, congestive heart failure, end-stage renal disease and pre-eclampsia. We also discuss potential therapeutic strategies that have emerged as a result of the increased understanding of the regulation and actions of cardiotonic steroids.     

The importance of basic science and clinical research as a selection criterion for general surgery residency programs

OBJECTIVE: The selection criteria for surgical residents applying for residency differ among programs nationwide. Factors influencing this selection process have not been well defined, and research in particular has not been evaluated fully. This study aimed to evaluate the relative importance of basic science and clinical research in the selection criteria used by program directors (PDs). DESIGN: A web-based survey consisting of 11 questions was sent to PDs using the list server of the Association of Program Directors in Surgery. Respondents were asked to rank selection factors using a 1-to-5 scoring system, with 5 as most important. Their responses were recorded and tabulated. SETTING: University-based teaching hospital. PARTICIPANTS: The survey went to 251 accredited general surgery residency programs in the United States. RESULTS: Overall, 134 (53.3%) of the surveys were returned, representing 61 university-based programs, 57 community-based programs with university affiliation, and 16 community-based programs without university affiliation. In total, 120 PDs (89.5%) considered basic or clinical research almost always or all the time when evaluating applicants to their general surgery program. Another 73 PDs (54.5%) gave basic science and clinical research equal importance. Another 40 PDs (29.9%) rarely or never credited research unless it had been published as an abstract or paper. In ranking research, 11 (8.2%) respondents gave it the 5 score. Most respondents (n = 93; 69.4%) gave it the 3 score. An applicant's interview and interest in surgery were the factors considered most important by 93 (69.4%) and 78 (58.2%), respectively, of the PDs. CONCLUSIONS: Basic science and clinical research constituted an important but secondary criterion for resident selection by PDs into general surgery residency programs. PDs perceived the primary factors for residency selection to be the interview, demonstrated interest in surgery, AOA membership, letters of recommendation, and USMLE Step I scores.     

Hospitalist performance of cardiac hand-carried ultrasound after focused training

Purpose

Because the training that noncardiologists require to perform cardiac hand-carried ultrasound has not been defined, we studied how well hospitalists perform hand-carried echocardiography after limited training.

Methods

Ten hospitalists completed a focused training program that included performing an average of 35 hand-carried echocardiograms. Hospitalists’ echocardiograms were compared with gold-standard conventional echocardiograms, and hospitalists were compared with 5 certified echocardiography technicians in their ability to acquire, measure, and interpret hand-carried ultrasound images and with 6 senior cardiology fellows in their ability to interpret echocardiograms.

Results

Echocardiography technicians had significantly higher performance scores for image acquisition, measurement, and interpretation than hospitalists. Senior cardiology fellows outperformed hospitalists in most aspects of image interpretation. For hospitalists, learning image acquisition was more difficult than image interpretation.

Conclusions

Hospitalists can learn aspects of hand-carried echocardiography, but after 35 training echocardiograms cannot replicate the quality of conventional echocardiography. Whether the lower performance skills are important will depend on the clinical context of hand-carried echocardiography performed by hospitalists.     

Selective endothelin A receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease

INTRODUCTION: Endothelin receptor antagonism has become an important component in the treatment of pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD). The purpose of this study was to analyse the safety and effectiveness of sitaxsentan, a selective antagonist of the ET(A) receptor, in a cohort of patients with PAH and CTD. Short-term clinical and haemodynamic effects and longer-term follow-up data are presented. METHODS: A post hoc subgroup analysis was performed on 42 patients who had PAH associated with CTD, out of a group of 178 patients enrolled in a 12-week, double-blind, randomised clinical trial of sitaxsentan versus placebo. Data from 33 patients assigned to sitaxsentan 100 mg or 300 mg daily were pooled and compared with nine placebo-treated patients. There were 41 patients entered into the blinded extension study, in which all patients received either 100 mg or 300 mg sitaxsentan once daily. RESULTS: Patients treated with sitaxsentan had a mean (SD) increase in 6 minute walk distance of 20 (5) m from baseline to week 12 (p = 0.037), whereas the placebo group had a decrease of 38 (84) m, resulting in a placebo-subtracted treatment effect of 58 m (p = 0.027). Parallel improvements in quality of life and haemodynamics were also observed. No patient discontinued their drug during the 12-week trial. In the blinded extension study (median treatment duration 26 weeks), more patients were in functional class I-II than in III-IV (p<0.001) at the end of the study compared with the start of active therapy. Elevation of hepatic transaminase levels occurred in two patients. CONCLUSIONS: Sitaxsentan appears to be efficacious in patients with PAH associated with CTD.     

Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors

Purpose MAC-321 is a novel taxane that has demonstrated exceptional activity in human xenograft models when administered intravenously and orally. Preclinical studies of MAC-321 have shown antitumor activity in MDR-expressing and paclitaxel-resistant tumors. This phase I dose escalation study was performed to determine the safety, tolerability, and pharmacokinetic profile of orally administered MAC-321 given once every 21 days. Preliminary antitumor activity of MAC-321 was also examined. Methods Key eligibility criteria included adult subjects with refractory solid tumors or solid tumors for which conventional therapy was unsuitable or did not exist, good performance status (ECOG ( 2), and adequate hematologic, hepatic, and renal functions. Plasma pharmacokinetic (PK) sampling was performed during the first cycle of therapy. Results Five dose levels of MAC-321 ranging from 25 to 75 mg/m² were evaluated in 18 subjects (four women and 14 men). MAC-321 was well tolerated at the first three dose levels (25, 37, 50 mg/m²). Two subjects developed dose-limiting toxicities (DLTs) at 75 mg/m²; one subject with grade 3 and one subject with grade 4 neutropenia with fever. Three subjects treated at an intermediate dose level of 60 mg/m² had no DLTs. However, the study was terminated prior to completion of the maximal tolerated dose cohort after subjects treated with intravenous MAC-321 in a concurrent study experienced life-threatening toxicities. Other common toxicities included grades 1–2 fatigue and grades 1–2 diarrhea. There was substantial interpatient variability in the PK parameters. MAC-321 was rapidly absorbed with a mean C _max value of less than 1 h. Mean C _max and AUC values generally increased in a dose-related manner. The median terminal phase elimination half-life was 45 h (range 20–228 h). Disease stabilization was seen in four subjects with the following tumors: mesothelioma (14 cycles), chondrosarcoma (12 cycles), small cell carcinoma (10 cycles), and prostate carcinoma (6 cycles). Conclusions MAC-321 can be safely administered orally once every 21 days up to a dose of 60 mg/m². The major DLT was neutropenic fever. Four subjects had disease stabilization.