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Background and Objective Zibotentan, a selective endothelin A receptor antagonist, is in development for chronic liver and kidney disease. The pharmacokinetics (PK) of zibotentan were previously investigated in patients with either renal impairment or hepatic impairment, but the impact of both pathologies on PK was not evaluated. This study evaluated the PK and tolerability of a single oral dose of zibotentan in participants with concurrent moderate renal impairment and moderate hepatic impairment versus control participants. Methods Twelve participants with moderate renal and hepatic impairment and 11 healthy matched control participants with no clinically significant liver or kidney disease were enrolled in an open-label, parallel-group study design. After administration of a single oral dose of zibotentan 5 mg, blood and urine sampling was performed. Pharmacokinetic parameters were determined for each of the two cohorts and compared. Comparisons between the cohorts were based on the geometric least squares mean ratio for the primary endpoints, which were area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC ∞ ) and from time zero to the time of the last measurable concentration (AUC last ), and maximum plasma drug concentration ( C max ) on Day 1 through 120 h post-dose. Secondary endpoints included apparent total body clearance (CL/F) on Day 1 through 120 h post-dose. Safety endpoints were assessed up to discharge. Results In total, 11 participants with concurrent moderate renal and hepatic impairment, and 11 controls, completed the study. Zibotentan was generally well tolerated, and no new clinically significant safety findings were observed. Total exposure (AUC ∞ and AUC last ) was approximately 2.10-fold higher in participants with concurrent moderate renal and hepatic impairment versus controls, while C max and total nonrenal body clearance were similar among all groups. A regression-based post hoc analysis, comparing exposure and CL/ F in patients with concurrent impairment to patients with either renal or hepatic impairment alone, showed that CL/ F with concurrent impairment was approximately half of that in controls and was positively correlated with reduction of renal function. Inclusion of the data on concurrent moderate renal and hepatic impairment in the regression analysis led to a narrower confidence interval for the predicted mean CL/ F in participants with moderate hepatic impairment. Conclusion The presented findings advance the understanding of the PK of zibotentan in both renal impairment and hepatic impairment, with and without overlapping pathologies, and will thus increase the confidence of dose selection in future studies, particularly in vulnerable patient populations with concurrent renal and hepatic impairment. Trial Registration ClinicalTrials.gov identifier: NCT05112419.

In this report of two randomized trials, patients with type 2 diabetes at risk for cardiovascular disease received the sodium–glucose cotransporter 2 inhibitor canagliflozin or placebo and were followed for 188 weeks. Canagliflozin reduced the risk of cardiovascular events.

Cardiac Abnormalities in Diabetic Patients With Neuropathy Effects of aldose reductase inhibitor administration Brian F. Johnson , MD 1 , Richard W. Nesto , MD 2 , Michael A. Pfeifer , MD 3 , William R. Slater , MD, FACC 4 , Aaron I. Vinik , MD 5 , Deborah A. Chyun , RN, PHD 6 , Gordon Law , PHD 1 , Frans J.Th. Wackers , MD 7 and Lawrence H. Young , MD 7 1 Pfizer Research, Groton, Connecticut 2 Department of Cardiovascular Medicine, Lahey Clinic, Burlington, Massachusetts 3 Department of Internal Medicine (Endocrinology and Metabolism), East Carolina Medical School, Greenville, North Carolina 4 Department of Internal Medicine (Cardiology), New York University Medical School, New York, New York 5 Strelitz Diabetes Institute, Eastern Virginia Medical School, Norfolk, Virginia 6 Yale University School of Nursing, New Haven, Connecticut 7 Department of Internal Medicine (Cardiovascular Medicine), Yale University School of Medicine, New Haven, Connecticut Address correspondence and reprint requests to Lawrence H. Young, MD, Yale University School of Medicine, 333 Cedar Street, FMP 3, New Haven, CT 06520. E-mail: lawrence.young{at}yale.edu Abstract OBJECTIVE —The goal of this study was to determine whether treatment with an aldose reductase inhibitor (ARI) has beneficial effects on asymptomatic cardiac abnormalities in diabetic patients with neuropathy. RESEARCH DESIGN AND METHODS —Diabetic subjects with neuropathy ( n = 81) with either a low diastolic peak filling rate or impaired augmentation of left ventricular (LV) ejection fraction (LVEF) during maximal bicycle exercise were identified by gated radionuclide ventriculography. Coronary artery disease, left ventricular hypertrophy, and valvular heart disease were excluded by clinical evaluation, myocardial perfusion imaging, and echocardiography. Subjects were randomized to receive blinded treatment with either the placebo or the ARI zopolrestat 500 or 1,000 mg daily for 1 year. RESULTS —After 1 year of ARI treatment, there were increases in resting LVEF ( P < 0.02), cardiac output ( P < 0.03), LV stroke volume ( P < 0.004), and exercise LVEF ( P < 0.001). In placebo-treated subjects, there were decreases in exercise cardiac output ( P < 0.03), stroke volume ( P < 0.02), and end diastolic volume ( P < 0.04). Exercise LVEF increased with ARI treatment independent of blood pressure, insulin use, or the presence of baseline abnormal heart rate variability. There was no change in resting diastolic filling rates in either group. CONCLUSIONS —Diabetic patients with neuropathy have LV abnormalities that can be stabilized and partially reversed by ARI treatment. ARI, aldose reductase inhibitor CAD, coronary artery disease EDV, end diastolic volume HF, heart failure LV, left ventricular LVEF, left ventricular ejection fraction PFR, peak filling rate Footnotes B.J. holds stock in Pfizer and was employed by Pfizer Research until retirement in February 2002. G.L. holds stock in and is employed by Pfizer Research. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted October 20, 2003. Received May 15, 2003. DIABETES CARE

Action research is a way of thinking, understanding, and promoting change by involving those directly affected in altering current practice or developing new practice. This article presents examples of action research as a \"bottom-up\" approach that involves and empowers supervisees. \"Top-down\" approaches are usually model specific and stem from the practice, theory, and philosophy of supervision espoused by a supervisor relative to the context in which the supervision takes place. Holloway's (1995, 1999) systems approach to supervision is reviewed as an example of a metatheoretical model that integrates bottom-up and top-down approaches. An exemplar of action research based on the Holloway model raises questions for consideration by transactional analysis supervisors.

The goal of this study was to determine whether treatment with an aldose reductase inhibitor (ARI) has beneficial effects on asymptomatic cardiac abnormalities in diabetic patients with neuropathy. Diabetic subjects with neuropathy (n = 81) with either a low diastolic peak filling rate or impaired augmentation of left ventricular (LV) ejection fraction (LVEF) during maximal bicycle exercise were identified by gated radionuclide ventriculography. Coronary artery disease, left ventricular hypertrophy, and valvular heart disease were excluded by clinical evaluation, myocardial perfusion imaging, and echocardiography. Subjects were randomized to receive blinded treatment with either the placebo or the ARI zopolrestat 500 or 1,000 mg daily for 1 year. After 1 year of ARI treatment, there were increases in resting LVEF (P < 0.02), cardiac output (P < 0.03), LV stroke volume (P < 0.004), and exercise LVEF (P < 0.001). In placebo-treated subjects, there were decreases in exercise cardiac output (P < 0.03), stroke volume (P < 0.02), and end diastolic volume (P < 0.04). Exercise LVEF increased with ARI treatment independent of blood pressure, insulin use, or the presence of baseline abnormal heart rate variability. There was no change in resting diastolic filling rates in either group. Diabetic patients with neuropathy have LV abnormalities that can be stabilized and partially reversed by ARI treatment.

Cold type composition is a method of producing typescript and/or graphic information by means of inputting coded text into core memory and retrieving via programs written to highlight or extract specific elements of text. Such technology represents a significant advancement in information transfer because of 1. the incredible speed with which “printed” matter may be produced, and 2. the variety of publications made possible by massaging data bases already converted to machine readable form. This paper examines the two fundamentally different technologies of “CRT” and “Photon” composition in order to analyze their impact on library and information science. The author concludes we are on the verge of an information revolution which will allow for integration of knowledge to an unprecedented degree…provided the information community becomes aware of these implications, and rigorously questions present means of bibliographic control.

Was it a good match? Contrary to the scoreline, it was good game, with a lot of endeavour from both sides. Both created chances, both clearly wanted the win, but neither had their shooting boots on. It's our sixth successive clean sheet at home. [Dougie Freedman] has got the team much tighter at the back and that's where we've got to build from. Who played well/who had a nightmare? Sean Scannell impressed with probing runs down the right and forced a good save. Darren Ambrose wasn't up to his usual high standards.

Neil Warnock believes that turning Palace from cannon fodder into play-off hopefuls is the biggest feat of his time as a manager. When Warnock replaced Peter Taylor in October, Palace were 19th in the Championship. They are now three games away from a place in the Premier League.