A history of opioid abuse: Why buprenorphine is superior for the management of opioid use disorder and pain.

Opioid abuse represents a public health crisis that has significant associated morbidity and mortality. Since beginning in the early 1990's, the opioid abuse epidemic has been difficult to control due to regulatory, economic, and psychosocial factors that have perpetuated its existence. This era of opioid abuse has been punctuated by three distinct rises in mortality, precipitated by unique public health problems that needed to be addressed. Patients affected by opioid abuse have been historically treated with either methadone or naltrexone. While these agents have clinical utility supported by robust literature, we the authors posit that buprenorphine is a superior therapy for both opioid use disorder (OUD) as well as pain. This primacy is due to the pharmacological properties of buprenorphine which render it unique among other opioid medications. One such property is buprenorphine's ceiling effect of respiratory depression, a common side effect and complicating factor in the administration of many classical opioid medications. This profile renders buprenorphine safer, while simultaneously retaining therapeutic utility in the medical practitioner's pharmacopeia for the treatment of opioid use disorder and pain.

Correction: Inhibition of NAPDH Oxidase 2 (NOX2) Prevents Oxidative Stress and Mitochondrial Abnormalities Caused by Saturated Fat in Cardiomyocytes.

[This corrects the article DOI: 10.1371/journal.pone.0145750.].

Inhibition of NAPDH Oxidase 2 (NOX2) Prevents Oxidative Stress and Mitochondrial Abnormalities Caused by Saturated Fat in Cardiomyocytes.

Obesity and high saturated fat intake increase the risk of heart failure and arrhythmias. The molecular mechanisms are poorly understood. We hypothesized that physiologic levels of saturated fat could increase mitochondrial reactive oxygen species (ROS) in cardiomyocytes, leading to abnormalities of calcium homeostasis and mitochondrial function. We investigated the effect of saturated fat on mitochondrial function and calcium homeostasis in isolated ventricular myocytes. The saturated fatty acid palmitate causes a decrease in mitochondrial respiration in cardiomyocytes. Palmitate, but not the monounsaturated fatty acid oleate, causes an increase in both total cellular ROS and mitochondrial ROS. Palmitate depolarizes the mitochondrial inner membrane and causes mitochondrial calcium overload by increasing sarcoplasmic reticulum calcium leak. Inhibitors of PKC or NOX2 prevent mitochondrial dysfunction and the increase in ROS, demonstrating that PKC-NOX2 activation is also required for amplification of palmitate induced-ROS. Cardiomyocytes from mice with genetic deletion of NOX2 do not have palmitate-induced ROS or mitochondrial dysfunction. We conclude that palmitate induces mitochondrial ROS that is amplified by NOX2, causing greater mitochondrial ROS generation and partial depolarization of the mitochondrial inner membrane. The abnormal sarcoplasmic reticulum calcium leak caused by palmitate could promote arrhythmia and heart failure. NOX2 inhibition is a potential therapy for heart disease caused by diabetes or obesity.