Design and synthesis of tri-ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K

We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.     

Bidirectional Relations of Impulsive Personality and Alcohol Use Across Three Waves of Data Collection

Objective: To explore the bidirectional relations between alcohol use and three impulsive personality traits, to advance understanding of risk processes. Participants: 525 college students (mean age = 18.95 years) recruited in August 2008 and 2009 and followed up annually for three years. Methods: Personality and past/current substance use were assessed. Results: T2 sensation seeking mediated the predictive relationship between T1 and T3 alcohol use, and T2 alcohol use mediated the predictive relationship between T1 and T3 sensation seeking. In addition, T2 alcohol problems mediated the predictive relationship between T1 alcohol use and T3 negative urgency. Conclusions: Findings support a bidirectional relationship between sensation seeking and alcohol use, and drinking anticipates drinking problems, which predict increases in negative urgency. For some individuals, there appears to be an ongoing process of increased risk in the form of increases in both drinking and high-risk personality traits.     

Safe and Appropriate Use of Methadone in Hospice and Palliative Care: Expert Consensus White Paper

Methadone has several unique characteristics that make it an attractive option for pain relief in serious illness, but the safety of methadone has been called into question after reports of a disproportionate increase in opioid-induced deaths in recent years. The American Pain Society, College on Problems of Drug Dependence, and the Heart Rhythm Society collaborated to issue guidelines on best practices to maximize methadone safety and efficacy, but guidelines for the end-of-life scenario have not yet been developed. A panel of 15 interprofessional hospice and palliative care experts from the U.S. and Canada convened in February 2015 to evaluate the American Pain Society methadone recommendations for applicability in the hospice and palliative care setting. The goal was to develop guidelines for safe and effective management of methadone therapy in hospice and palliative care. This article represents the consensus opinion of the hospice and palliative care experts for methadone use at end of life, including guidance on appropriate candidates for methadone, detail in dosing, titration, and monitoring of patients' response to methadone therapy.     

Mechanical,inflammatory, and embolic complications of myocardial infarction: An emergency medicine review

IntroductionDespite the declining incidence of coronary heart disease (CHD) in the United States, acute myocardial infarction (AMI) remains an important clinical entity, with many patients requiring emergency department (ED) management for mechanical, inflammatory, and embolic complications.ObjectiveThis narrative review provides an evidence-based summary of the current data for the emergency medicine evaluation and management of post myocardial infarction mechanical, inflammatory, and embolic complications.DiscussionWhile 30-day mortality rate after AMI has decreased in the past two decades, it remains significantly elevated at 7.8%, owing to a wide variety of subacute complications evolving over weeks. Mechanical complications such as ventricular free wall rupture, ventricular septal rupture, mitral valve regurgitation, and formation of left ventricular aneurysms carry significant morbidity. Additional complications include ischemic stroke, heart failure, renal failure, and cardiac dysrhythmias. This review provides several guiding principles for management of these complications. Understanding these complications and an approach to the management of various complications is essential to optimizing patient care.ConclusionsMechanical, inflammatory, and embolic complications of AMI can result in significant morbidity and mortality. Physicians must rapidly diagnose these conditions while evaluating for other diseases. In addition to understanding the natural progression of disease and performing a focused physical examination, an electrocardiogram and bedside echocardiogram provide quick, noninvasive determinations of the underlying pathophysiology. Management varies by presentation and etiology, but close consultation with cardiology and cardiac surgery is recommended.     

A unique case of bradycardia recognized by wearable technology as first presentation of complete heart block

Wearable technology has advanced significantly, and the proposed health benefits have been widely touted. Most of the discussion has been surrounding the identification and diagnosis of asymptomatic atrial fibrillation. However, the heart monitoring functions of the wearable technology can also identify other abnormalities as well. We present the first case of wearable technology identified bradycardia diagnosed as the primary presentation of complete heart block. Wearable technology has advanced significantly, but still poses questions regarding its use in screening for rare conditions. One remaining challenge is balancing the desire to screen for rare asymptomatic conditions without overburdening emergency departments with patients responding to alarms on their devices.