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Serious mental illnesses (SMIs), including schizophrenia, bipolar disorder, and major depressive disorder (MDD), are often treated with antipsychotic medications. Unfortunately, medication non-adherence is widespread and is associated with serious adverse outcomes. However, little real-world data are available describing adherence, compliance, or other medication-taking-related discussions between providers and patients. This study described these communications in ambulatory care.Commercially insured patients having acute (emergency or inpatient) behavioral health (BH) events were included by specific criteria: age 18-65 years; diagnoses of schizophrenia, bipolar disorder, or MDD; continuous health insurance coverage 6 months before to 12 months after the first claim (index) date during 01/01/2014‒12/31/2015; and prescribed antipsychotic medication. Medical charts were abstracted for ambulatory visits with a BH diagnosis through 12 months after the acute event, describing any treatment compliance discussions that occurred. BH-related healthcare utilization and costs were measuredNinety patients were included: 62% female, mean age 41 years. Only 58% had antipsychotic compliance discussions during the first abstracted ambulatory visit. A total of 680 BH-related visits were abstracted for the 90 patients. Providers frequently discussed any psychotropic medication use (97% of all visits abstracted); however, discussion of compliance with BH talk therapies was less common (49% of visits among patients with a first visit antipsychotic discussion and 23% without,Increasing the frequency of antipsychotic treatment-related adherence/compliance discussions may represent an opportunity to improve the quality of care for these vulnerable patients and reduce the overall economic burden associated with the treatment of SMI diagnosis.

Background Addition of a long-acting muscarinic antagonist is recommended for patients with asthma uncontrolled on inhaled corticosteroid/long-acting β2-agonist therapy. This is the first large-scale, real-world study examining multiple-inhaler triple-therapy (MITT) use in asthma. Objective To describe real-world prevalence, outcomes, and treatment patterns associated with MITT. Methods This retrospective cohort study used medical and pharmacy claims from the Optum Research Database. Patients were diagnosed with asthma between January 01, 2013, and July 31, 2018, with evidence of MITT use (≥1 overlapping days' supply of inhaled corticosteroid, long-acting β2-agonist, and long-acting muscarinic antagonist). Annual MITT prevalence (primary end point) was assessed in the prevalent population; eligible patients were 18 years or older with 2 or more asthma diagnoses during the study period, and continuous enrollment for the entire year. Secondary outcomes (adherence [proportion of days covered], MITT persistence, health care resource utilization, costs) were assessed in the incident MITT population; eligible patients were 18 years or older, with 2 or more asthma diagnoses and continuous enrollment during both the 12-month baseline and 12-month follow-up periods. Patients with chronic obstructive pulmonary disease or cystic fibrosis were excluded. Results MITT prevalence was low but increased from 0.35% (95% CI, 0.32-0.37) in 2014/2015 to 1.00% (95% CI, 0.96-1.04) in 2017/2018. Among 1831 incident MITT users, there was a substantial disease burden, demonstrated by high health care resource utilization and exacerbation rates. Adherence and persistence to MITT was low (mean proportion of days covered, 0.31 ± 0.27), and 12% (n = 216) remained on MITT 12 months postinitiation. Conclusions Overall, MITT use among patients with asthma is low. Patients initiating MITT have substantial disease burden and significant unmet needs.

Despite the potential for the chemokine class as therapeutic targets in immune mediated disease, success has been limited. Many chemokines can bind to multiple receptors and many receptors have multiple ligands, with few exceptions. One of those exceptions is CCL20, which exclusively pairs to CCR6 and is associated with several immunologic conditions, thus providing a promising therapeutic target. Following successful evaluation in a single dose, first time in human clinical study, GSK3050002-a humanized IgG1 monoclonal antibody against human CCL20-was evaluated in a 26-week cynomolgus monkey toxicology study. A high incidence of unexpected vascular and organ inflammation was observed microscopically, leading to the decision to halt clinical development. Here we report a dose-responsive increase in the incidence and severity of inflammation in multiple organs from monkeys receiving 30 and 300 mg/kg/week by either subcutaneous or intravenous injection. Histomorphological changes resembled an immune complex-mediated pathology, which is often due to formation of anti-drug antibodies in monkeys receiving a human protein therapeutic and thus not predictive of clinical outcome. However, the presentation was atypical in that there was a clear dose response with a very high incidence of inflammation with a low incidence of ADA that did not correlate well individually. Additionally, the immunohistologic presentation was atypical in that the severity and distribution of tissue inflammation was greater than the numbers of associated immune complexes (i.e., granular deposits). An extensive ex vivo analysis of large molecular weight protein complexes in monkey serum from this study and in human serum samples demonstrated a time-dependent aggregation of GSK3050002, that was not predicted by in vitro assays. The aggregates also contained complement components. These findings support the hypothesis that immune complexes of drug aggregates, not necessarily including anti-drug antibodies, can fix complement, accumulate over time, and trigger immune complex disease. A situation which may have increased clinical relevance than typical anti-drug antibody-associated immune complex disease in monkeys administered human antibody proteins.

Objective: To provide an overview of the differences between biosimilars and generics, and to summarize regulatory requirements and outstanding issues related to biosimilar insulins in the United States, including the issue of interchangeability. Data Sources: References were obtained using MEDLINE searches, the bibliographies of articles identified during the searches, review articles, and general Internet searches. Key words included the following: diabetes, insulin, biosimilar, regulatory, follow-on, and interchangeability. Study Selection and Data Extraction: Articles, studies, regulatory documents, and opinion pieces that addressed issues around biosimilar/follow-on insulins and interchangeability of insulins in people with diabetes were selected for inclusion in this narrative review. Data Synthesis: There is understandable interest in the potential for new copies of existing insulins—termed biosimilar insulins or follow-on insulins—to reduce the substantial and growing costs associated with managing the diabetes epidemic and to improve access, as has been achieved with conventional generic drugs. However, biosimilars or follow-on insulins are not generics. There are critical differences between biologic products and conventional chemical drugs, which present specific challenges to manufacturers, regulators, and clinicians. Conclusions: Health care providers and payers need to be aware of the issues surrounding biosimilar and follow-on insulins as they become more widely available in the coming years. In particular, in the face of limited data on comparative safety and efficacy, careful consideration needs to be given when interchanging between originator and biosimilar drugs, when switching patients from one biosimilar drug to the other.

This post hoc analysis of gastrointestinal (GI) adverse events (AEs) from the phase 3 LixiLan-L (NCT02058160) and LixiLan-O (NCT02058147) trials aimed to determine the frequency and timing of nausea, vomiting, and diarrhoea for iGlarLixi, a titratable, fixed-ratio combination of insulin glargine 100 units/mL (iGlar) and lixisenatide, versus iGlar alone or iGlar and lixisenatide alone, in patients with type 2 diabetes uncontrolled with oral antidiabetes drugs (OADs) or basal insulin ± OADs. In iGlarLixi-treated patients, the rate of GI AEs during the initial weeks of treatment was lower versus patients treated with lixisenatide alone (9.6% and 11.7% of iGlarLixi-treated patients in LixiLan-L and LixiLan-O, respectively, vs. 27.5% of lixisenatide-treated patients in LixiLan-O). Beyond day 60, these rates were generally low and similar to those of lixisenatide. These lower rates are likely due to the gradual titration of lixisenatide in iGlarLixi. Median durations of intermittent GI AEs in the iGlarLixi arms were 6.0, 2.0 and 2.5 days (LixiLan-L), and 5.0, 1.0 and 3.5 days (LixiLan-O), respectively. iGlarLixi-associated GI AEs were transient, mostly mild or moderate in severity, and occurred mainly during initial titration.

IN BRIEF Titratable fixed-ratio combinations (FRCs) of a basal insulin and a glucagon-like peptide-1 (GLP-1) receptor agonist are new therapeutic options for people with type 2 diabetes. Two FRCs—insulin degludec/liraglutide and insulin glargine/lixisenatide—have been approved for use in the United States. The two components in these FRCs target different aspects of diabetes pathophysiology, working in a complementary manner to decrease blood glucose while mitigating the side effects associated with each component (hypoglycemia and weight gain with insulin and gastrointestinal side effects with GLP-1 receptor agonists). This article reviews these products and key considerations for their use.

Despite the availability of 12 different classes of medications, many people with type 2 diabetes struggle to maintain glycemic control (1). Among the many new antidiabetic medications to have emerged in recent years, sodium–glucose cotransporter 2 (SGLT2) inhibitors have proved to be a particularly effective oral treatment for these patients (2). Since the approval of the first drug in this class, canagliflozin, by the U.S. Food and Drug Administration (FDA) in March 2013, a total of four SGLT2 agents have become available (both as single and fixed-dose combination formulas) (1). In 2017, an estimated 1.7 million patients received a dispensed prescription for an SGLT2 inhibitor from U.S. outpatient retail pharmacies (2). Ertugliflozin is the newest agent among these, having received FDA approval in December 2017 (3). Ertugliflozin is indicated as an adjunct to diet and exercise for control of hyperglycemia in adults (≥18 years of age) with type 2 diabetes (4). It can be used as monotherapy in patients for whom metformin is contraindicated or not well tolerated. It can also be used in combination with other antidiabetic agents (most commonly metformin or a dipeptidyl peptidase 4 [DPP-4] inhibitor) to help reduce A1C. Currently, ertugliflozin is available as an oral tablet sold under the brand name Steglatro or in oral tablet combinations with the DPP-4 sitagliptin (brand name …

Easy-to-use naloxone formulations are needed to help address the opioid overdose epidemic. The pharmacokinetics of i.v., i.m., and a new i.n. naloxone formulation (2 mg) were compared in six healthy volunteers. Relative to i.m. naloxone, geometric mean (90% confidence interval [CI]) absolute bioavailability of i.n. naloxone was modestly lower (55%; 90% CI, 43-70% vs. 41%; 90% CI, 27-62%), whereas average (±SE) mean absorption time was substantially shorter (74 ± 8.8 vs. 6.7 ± 4.9 min). The opioid-attenuating effects of i.n. naloxone were compared with i.m. naloxone (2 mg) after administration of oral alfentanil (4 mg) to a separate group of six healthy volunteers pretreated with 240 mL of water or grapefruit juice. The i.m. and i.n. naloxone attenuated miosis by similar extents after water (40 ± 15 vs. 41 ± 21 h*%) and grapefruit juice (49 ± 18 vs. 50 ± 22 h*%) pretreatment. Results merit further testing of this new naloxone formulation.

Hypoglycemia is a common side effect of diabetes treatment. Severe hypoglycemia is both potentially dangerous and costly to patients and the health care system. It occurs frequently in patients treated with intensive insulin therapy but can also occur in anyone treated with other hypoglycemic agents. Glucagon is a polypeptide produced by the α-cells in pancreatic islets (1). It stimulates the breakdown of glycogen in the liver with the resultant liberation of glucose, which increases the plasma glucose concentration. Currently, the only available glucagon formulation on the market for the treatment of severe hypoglycemia is injectable glucagon (subcutaneous, intramuscular). However, glucagon is unstable when in solution and so requires reconstitution before administration. This process can be stressful for both patients and caregivers during hypoglycemic emergencies. Nasal glucagon has been shown to be as efficacious as the intramuscular glucagon formulation. Recently, Eli Lilly submitted a new drug application seeking approval of nasal glucagon from the U.S. Food and Drug Administration and the European Medicines Agency. If approved, this agent will be …

Objective: To review 2 new basal insulin analogs that have been approved in the United States for use in type 1 and type 2 diabetes—insulin glargine 300 units/mL and insulin degludec 100 units/mL and 200 units/mL. Data Sources: PubMed was searched using the terms “insulin glargine 300 units/mL,” “Gla-300,” “insulin degludec,” “IDeg,” “insulin degludec 200 units/mL,” and “insulin degludec 100 units/mL” for articles published between 1995 and May 2016. Study Selection and Data Extraction: Clinical trials, meta-analyses and subanalyses were identified; review articles were excluded. Relevant citations from identified articles were also reviewed. Data Synthesis: The new basal insulins, insulin glargine 300 units/mL and insulin degludec 100 units/mL and 200 units/mL, have improved pharmacokinetic and pharmacodynamic profiles compared to insulin glargine 100 units/mL. All demonstrate longer durations of action, beyond 24 hours, and less variability. These improved profiles translate into comparable A1C reductions and comparable, or improved, levels of hypoglycemia compared to insulin glargine 100 units/mL. Conclusions: These benefits may lead to improved glycemic control in a range of patients with type 1 and type 2 diabetes with true once-daily dosing.

In Brief New insulin glargine 300 units/mL (Gla-300) is a formulation of insulin glargine that has a more constant pharmacokinetic profile with a prolonged duration of action. The EDITION clinical trial program showed that the use of Gla-300 leads to glycemic control comparable to that of insulin glargine 100 units/mL in a wide range of populations of people with diabetes. It is associated with comparable to less nocturnal confirmed or severe hypoglycemia and less weight gain, despite requiring a somewhat higher insulin dose than U-100. The distinct pharmacokinetic/pharmacodynamic and clinical profiles of Gla-300 may benefit a range of people with type 1 or type 2 diabetes.

The caffeine metabolic ratio is an established marker for cytochrome P450 (CYP) 1A2 activity. Optimal sample size calculation for clinical pharmacokinetic xenobiotic-caffeine interaction studies requires robust estimates of interindividual and intraindividual variation in this ratio. Compared with interindividual variation, factors contributing to intraindividual variation are less defined. An exploratory analysis involving healthy nonsmoking non-naive caffeine drinkers (1-3 cups/day; 12 men, 12 women) administered caffeine (160 mg) on five occasions evaluated the effects of CYP1A2 induction status (based on genotype) and other factors on intraindividual variation in CYP1A2 activity. Results were compared with those from previous studies. Regardless of whether a hyperinducer (CYP1A2*1A/*1F or CYP1A2*1F/*1F) or normal metabolizer (CYP1A2*1A/*1A, CYP1A2*1C/*1F, or CYP1A2*1C*1F/*1C*1F), sex, age, oral contraceptive use by women, and smoking status, intraindividual variation was ≤30%. A value of 30% is proposed for optimal design of pharmacokinetic xenobiotic-caffeine interaction studies. Prospective studies are needed for confirmation.

Objective: Asthma prevalence, especially among children, is increasing globally. Nearly 7.1 million children in the US currently have asthma. Given limited research on treatment patterns in the pediatric population, the aim of this study was to examine treatment regimens and adherence to the National Heart Lung and Blood Institute (NHLBI) stepwise approach for asthma management among pediatric patients. Methods: The study population included asthma patients < 12 years old initiating controller medication between 1/1/2011 and 2/28/2015 from a large US administrative claims database. Asthma was defined based on the presence …

Objective: To review available studies of empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission and the United States Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM). Data Sources: PubMed was searched using the search terms empagliflozin, BI 10773, and BI10773, for entries between January 1, 2000, and December 1, 2014. Reference lists from retrieved articles were searched manually for additional peer-reviewed publications. Study Selection and Data Extraction: All publications reporting clinical trials of empagliflozin were eligible for inclusion. Data Synthesis: Empagliflozin is a new once-daily oral SGLT2 inhibitor with a mechanism of action that is independent of β-cell function and the insulin pathway. Data from a comprehensive phase III clinical trial program have demonstrated its efficacy as monotherapy, as add-on to other glucose-lowering agents, and in different patient populations. In these studies, empagliflozin resulted in improvements in blood glucose levels as well as reductions in body weight and blood pressure. Empagliflozin was well tolerated and was not associated with an increased risk of hypoglycemia versus placebo. Conclusion: The oral antidiabetes agent, empagliflozin, can be used as monotherapy or alongside other glucose-lowering treatments, including insulin, to treat T2DM.

Successful adaptation to global environmental change will require confronting multiple unfolding challenges in concert. Coastal regions vulnerable to sea level rise and tropical storms will likely also be influenced by resource limitation in an uncertain future. In this paper, we explore the interrelated dynamics of coastal population migration, economic instability, and anthropogenic phosphorus (P) flows. Accounting for P flows and improving human P use efficiency are critical tasks given the finite global supply of phosphate rock and widespread eutrophication. We use material flow analysis to examine societal P metabolism in the Upper Pontchartrain Basin in coastal Louisiana, USA for two 5-y time periods (2001–2005 and 2006–2010) to capture the effects of fertilizer economics and population growth partially driven by the impact of Hurricane Katrina in the lower basin in 2005. Mass balances encompass human-mediated P fluxes in food production and consumption subsystems across agricultural, developed, and forested landscapes. Drastic reductions in locally purchased inorganic P fertilizer (78% decline between periods) were correlated to increases in fertilizer prices. Total P input to the study region decreased from 5452 to 3268 Mg P y−1 between periods. Changes in P flows were primarily driven by fertilizer economics, declining dairy production, and the influx of new residents, which has been characterized by decentralized settlement that limits P recycling. Societal P metabolic efficiency increased from 22% to 32% due largely to reduced fertilizer inputs. Leakage to the Pontchartrain Estuary and the Mississippi River represented 17–23% of total system P input, while the vast majority of P accumulated within soils, wastewater systems, and landfills. We discuss basin trends and management implications. A historic opportunity exists to encourage future coastal development characterized by synergies between local agriculture and human habitation to promote energy efficient nutrient recycling. The effect would be a decreased vulnerability to future fertilizer price spikes, along with the mitigation of current and future eutrophication.

Objective Responding to the nationwide opioid overdose epidemic, Washington State University initiated a naloxone safety net project intending to increase awareness of opioid overdose, increase the availability of naloxone, and examine university students' perceptions regarding the usefulness of a novel, large-group audience-training model. Setting A Washington State University campus. Practice description In September 2014, university students were recruited to attended a large-group audience training event which included opioid overdose prevention, recognition, and first response. All trained participants received an intranasal naloxone reversal kit. Practice innovation Student pharmacists, who previously received naloxone rescue training and overdose education from the pharmacist lead researcher, acted as trainers. The training consisted of a large-group audience delivery with small-group practice sessions facilitated by the student pharmacists. Evaluation Participants who attended the recruitment event completed a pre-training survey to assess knowledge and perceptions about opioid use disorder and overdose. The following week, participants attended the training event. Participants were asked to complete a post-training survey to evaluate the usefulness of the program. Results Forty-three percent of the participants (65/150) who attended the recruitment event reported knowing someone who used prescription opioids to get "high." Seventy-four participants attended the training, and 92% of them (68/74) completed the post-training survey. The majority of respondents agreed that the training program met their expectations and the skills they learned could be used to intervene in an overdose situation. Conclusions Before training, survey responses from recruited participates indicated the need to discuss opioid use disorder among university students is important. Use of a training model involving large-group audiences followed by small-group practice sessions offers an acceptable educational solution regarding opioid overdose and prevention. Our experience suggests using this training model to educate university students to recognize and provide first response is a feasible and acceptable approach.

A ccording to the American Diabetes Association, the direct and indirect costs of diabetes in the United States have exceeded $174 billion, and there are 25.8 million U.S. children and adults with diabetes.1 Numerous resources are available to help patients increase their role in the management of diabetes while simultaneously improving their metabolic parameters. Although the Internet is a burgeoning source of information and resources, the average patient often lacks the skills for finding and using the most optimal health care information.2 It is important for health care providers (HCPs) to educate patients about the available pragmatic technological resources for the management of their diabetes. Specifically, smartphones have become an integral component of daily life for many people in the United States. In 2011, > 85% of Americans owned and used a mobile phone, and half of those users also had Internet access with their mobile devices.3 The implementation of smartphone applications and tools for the management of diabetes may be an effective option in reducing the progression of diabetes and improving quality of life. Consistent self-monitoring blood glucose (SMBG) has been shown to be a useful tool in improving glycemic control in type 2 diabetes.4 The use of smartphone applications (“apps”) has already been shown to be a useful method for accurately logging and managing SMBG results. SMBG data that are logged on a smartphone app can be easily reviewed with HCPs to make recommendations about exercise, diet, or medications. A meta-analysis revealed that using SMBG data stored in and/or shared through a PDA (personal data assistant), logbook, the Internet, fax machines, and other innovative technologies, along with consistent feedback from an HCP, enhanced glycemic improvements and reduced hospitalizations.5 The goal of using smartphone apps is to effectively manage diabetes by improving glycemic control …

The aim of this paper is to evaluate the current status of municipal wastewater (MWW) treatment in Mexico, as well as to assess opportunities for using ecological treatment systems, such as constructed wetlands. In 2008, Mexico had 2101 MWW treatment plants that treated only 84 m3/s of wastewater (208 m3/s ofMWW were collected in sewer systems). Unfortunately, most treatment plants operate below capacity owing to a lack of maintenance and paucity of properly trained personnel. The main types of treatment systems applied in Mexico are activated sludge and waste stabilization ponds, which treat 44.3% and 18% of the MWW collected, respectively. As in many other developing nations around the world, there is a great need in Mexico for low-cost, low-maintenance wastewater treatment systems that are both economically and environmentally sustainable. In 2005, 24.3 million Mexicans lived in villages of less than 2500 inhabitants and 14.1 million lived in towns with 2500-15,000 inhabitants. An opportunity exists to extend the use of ecological treatment systems to these low population density areas and considerably increase the percentage of MWW that is treated in Mexico. Small-scale and medium-size constructed wetlands have been built successfully in some states, primarily during the past five years. Several barriers need to be overcome to increase the adoption and utilization of ecological wastewater technology in Mexico, including: a lack of knowledge about this technology, scarce technical information in Spanish, and the government's concentration on constructing MWW treatment plants solely in urban areas.

L ow-cost methods are desperately needed for improving diabetes management for people with diabetes in rural communities. With this understanding, the research team designed a project that used student pharmacists as coaches. High rates of diabetes and its complications in many rural communities point to these sites as diabetes hot spots.1 In Washington State's diabetes hot-spot communities, 17% of people > 45 years of age have diabetes on average, compared to 8.6% of people ≥ 45 years of age statewide. In one remote rural community, 40% of the population has diabetes. People in diabetes hot-spot communities also have higher rates of hospitalizations for severe diabetes complications. Controlling diabetes to reduce the incidence of its complications rests largely on individual patients and requires vigorous self-management of the disease.2 Unfortunately, without sustained support, few people achieve their goals or master the tasks that will allow them to live healthfully and reduce their risk of costly complications.3 Telephone follow-up for education and support has been shown to be a cost-effective method for improving healthy lifestyle behaviors in a variety of conditions, including diabetes.4-7 This project tested the use of brief telephone coaching sessions to improve the health of rural residents with diabetes by helping them achieve diabetes self-management goals for regular medical care and adherence to medication, diet, and physical activity regimens. Specifically, the research intent was to determine whether: 1. Participants would be better able to implement self-management tasks and reduce their risk of diabetes complications compared to a historical control group not receiving coaching, 2. Faculty and staff at the Washington State University (WSU) Extension and College of Pharmacy would be able to develop a telephone-coaching program to support additional lifestyle modifications after diabetes education to augment health care in rural areas, and 3. Telephone coaches would be …

Summary Aims Data from the EDITION 3 randomized study and the Clinformatics claims database were analysed to determine whether insulin glargine 300 U/mL (Gla‐300) could provide insulin‐naive patients with type 2 diabetes (T2D) on oral antidiabetes drugs (OADs) with reductions in prior OAD therapy without compromising glycaemic control, and while preserving its known low incidence of hypoglycaemia compared with insulin glargine 100 U/mL (Gla‐100). Methods Patient‐level data from EDITION 3 and de‐identified data from the Clinformatics real‐world claims database were analysed. Results At baseline, 70% of patients in EDITION 3 were on a background of ≥2 OADs. Among the 435 and 437 patients who initiated basal insulin with Gla‐300 and Gla‐100, respectively, at Month 6, 336 (77%) and 338 (77%) were using ≤1 OAD. Adding Gla‐300 or Gla‐100 similarly allowed for a reduction in background OAD medication in the Clinformatics dataset (N = 6430), such that, at 6 months postbasal insulin initiation, 14% of patients were no longer taking any OADs. In the analysis of the EDITION 3 study, reduction in OAD burden did not compromise glycaemic benefit, and the low incidence of hypoglycaemia associated with Gla‐300 compared with Gla‐100 was also preserved. Documented symptomatic hypoglycaemia (blood glucose ≤70 mg/dL) occurred in 30.5% vs 41.0% of patients treated with Gla‐300 and Gla‐100, respectively (P = 0.0442). Conclusion Patients with T2D who initiate basal insulin with Gla‐300 could potentially reduce their prior OAD use without compromising glycaemic control and with less hypoglycaemia than with Gla‐100.

IN BRIEF This article reviews the history of phlorizin, the role of the kidney in glucose regulation, and the modulation of that regulatory system via pharmacological means. It also offers a discussion of the results of clinical trials of the most salient sodium glucose co-transporter inhibitor to date: dapagliflozin.

The introductory differential equations course can be made more relevant to engineering students by including more of the engineering viewpoint, in which differential equations are regarded as systems with inputs and outputs. This can be done without sacrificing any of the usual topical coverage. This point of view is conducive to student exploration, which can be facilitated by software tools such as those available at http://dynsys.uml.edu/.

IN BRIEF Sitagliptin is the first agent in a new category of medications, the dipeptidyl peptidase-IV (DPP-IV) inhibitors. It was recently approved in the United States for the management of hyperglycemia in patients with type 2 diabetes; vildagliptin, a second agent in this class, is likely to join it on the U.S. market soon. These compounds accentuate the activity of endogenously produced antihyperglyemic incretin hormones and are generally well tolerated. This article provides an overview of the pharmacology and clinical use of the DPP-IV inhibitors.

Strong evidence exists demonstrating the benefits of tight glycemic control in type 1 and type 2 diabetes mellitus patients, but glycemic goals are not adequately achieved for many patients. Advancement in the knowledge surrounding the physiology of endogenous glucoregula- tory peptide hormones, such as glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, has led to new therapeutic targets for the treatment of type 2 diabetes mellitus. Dipeptidyl peptidase-4 (DPP-4) inhibitors provide practitioners with a novel mechanism of action to use for combination therapies for the treatment of type 2 diabetes mellitus. This article, part 3 of a 3-part series, reviews the new class of medications known as DPP-4 inhibitors as well as discusses a future buccal insulin formulation, Oral-Lyn™, on the horizon for the treatment of diabetes mellitus.

Hypoglycemia unawareness is defined as the onset of neuroglycopenia before the appearance of autonomic warning symptoms.1 It is difficult to study in its natural form because of its paroxysmal and unpredictable nature; therefore, well-controlled trials are limited. However, much is known regarding risk factors, biochemical causes, and populations at greatest risk for the development of hypoglycemia unawareness. Less is known regarding the impact of medications on the development or recognition of this condition in patients with diabetes. Several medications are thought to worsen or promote hypoglycemia unawareness, whereas others may have an attenuating effect on the problem. This article will review hypoglycemia unawareness and summarize the effects of medications that may influence it. In individuals without diabetes, a predictable, organized response occurs when blood glucose declines to hypoglycemic levels (Figure 1). First, insulin secretion is suppressed as glucose falls to < 81 mg/dl.1 The suppression of insulin secretion has two effects: peripheral glucose utilization is reduced and hepatic glucose output is induced. This action typically terminates the episode. However, if glucose decline continues to < 68 mg/dl, glucagon secretion from α-cells and epinephrine secretion from the adrenals are stimulated.1 These actions promote hepatic glucose production via gluconeogenesis and glycogenolysis. Growth hormone and cortisol are released as glucose levels decline even further (to ∼ 63 mg/dl) but are probably best characterized as responders to prolonged hypoglycemia rather than acute responders. The central nervous system triggers autonomic symptoms of hypoglycemia at plasma glucose levels between 54 and 90 mg/dl (Table 1). These symptoms are aimed at encouraging consumption of calories and are the harbinger of impending neuroglycopenia. If unchecked, the hypoglycemia will cause neuroglycopenic symptoms (Table 1) and eventually seizures and coma. View this table: Table 1. Symptoms of Hypoglycemia The glycemic threshold at which this counterregulatory response occurs is predictable in people without …

Objective: To describe the studies evaluating the efficacy and safety of new insulin glargine 300 U/mL (Gla-300) as a basal insulin in the treatment of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. Data Sources: A literature search of MEDLINE was conducted (January 2008-June 2015) using the terms U300, Gla-300, and insulin glargine 300 units/mL and supplemented with congress abstracts published in 2014 and 2015. Study Selection and Data Extraction: All English language studies assessing the efficacy and/or safety of Gla-300 were evaluated. Data Synthesis: The efficacy and safety of once-daily Gla-300 has been compared with insulin glargine 100 U/mL (Gla-100) in the EDITION trials, 6 phase-3, multinational, open-label studies in T1DM and T2DM. Across these studies, Gla-300 consistently demonstrated glycemic control comparable to Gla-100; a mean (standard error) change in glycated hemoglobin A1cof −1.02% (0.03) with both Gla-100 (n = 1235) and Gla-300 (n = 1239) was seen in a patient-level meta-analysis. Gla-300 was associated with comparable or reduced nocturnal hypoglycemia compared with Gla-100; the relative risk for nocturnal hypoglycemia with Gla-300 versus Gla-100 was 0.75 (95% CI = 0.68 to 0.83) in a patient-level meta-analysis. There is also some evidence for less weight gain with Gla-300 compared with Gla-100, despite a higher insulin dose. Gla-300 was well tolerated, with the number of adverse events being comparable to that with Gla-100. Conclusions: These results suggest that Gla-300 may have a place as an alternative, long-acting basal insulin for patients with T1DM or T2DM, with the possibility for improved tolerability.

A new method is presented which enables the identification of a reduced order nonlinear ordinary differential equation (ODE) which can be used to model the behavior of nonlinear fluid dynamics. The method uses a harmonic balance technique and proper orthogonal decomposition to compute reduced order training datawhich is then used to compute the unknown coefficients of the nonlinear ODE. The method is used to compute the Euler compressible flow solutions for the supercritical two-dimensional NLR-7301 airfoil undergoing both small and large pitch oscillationsatthreedifferentreducedfrequenciesandataMachnumberof0.764.Steadyanddynamicliftcoefficient datacomputedusingathreeequationreducedordersystemidentificationmodelcomparedwellwithdatacomputed using the full CFD harmonic balance solution. The system identification model accurately predicted a nonlinear trend in the lift coefficient results (steady and dynamic) for pitch oscillation magnitudes greater than 1 deg. Overall the reduction in the number of nonlinear differential equations was 5 orders of magnitude which corresponded to a 3 order of magnitude reduction in the total computational time.

RELAP5 is a system code developed at the Idaho National Environmental and Engineering Laboratory for thermal hydraulic analysis of nuclear reactors. The code RELAP5 is widely used for safety analysis studies of commercial nuclear power plants. However, recent released version of RELAP5/3.2 and over present significant capabilities for analysis of nuclear reactor research systems. As a contribution to the assessment of RELAP5/3.3 for research reactor safety analysis, experimental data from the University of Massachusetts Lowell Research Reactor - UMLRR are used. The UMLRR is a 1 MW light water moderated and cooled, graphite-reflected, open-pool type research reactor. This paper presents the development and the validation of a UMLRR-RELAP model using experimental data. For this purpose, a series of experiments were performed for benchmarking RELAP5 calculations for research reactor systems. As a result of this study, the UMLRR nodalization is shown to be representative of the experimental data reactor behavior.

SGLT2 inhibition offers a novel mechanism to mitigate hyperglycemia in patients with diabetes and the introduction of SGLT2 has added a significant new tool to the antihyperglycemic armamentarium. At present, 2 agents are approved for use in the United States and several more are in development. SGLT2 inhibitors are generally associated with a reduction in A1C of between 0.5% and 1%. SGLT2 inhibitors are associated with an increased incidence of urinary tract and genital infections but these infections are typically mild, responsive to treatment, and are not use limiting.

Flutter and limit-cycle oscillations(LCO) of a delta-wing model are studied theoretically and correlated with results from an earlier experiment and an earlier simpler theoretical model. The present theoretical model uses a high-fidelity nonlinear structural model and a linear vortex lattice aerodynamic model. The commercial finite element package ANSYS is selected to model the structure and is coupled to the vortex lattice aerodynamic model using a subiteration procedure to carry out time simulations. The delta-wing model is studied for five angles of attack (0, 1, 2, 3, and 4 deg) and for various flow speeds. Theoretical results are calculated for two different root-chord boundary conditions, that is, fully fixed and also another that allows some in-plane movement at the root chord by attaching stiff in-plane springs that connect the structure to the root boundary. The results obtained using the high-fidelity structural model are compared to earlier results computed using a lower-fidelity von Karman plate theory. For all angles of attack studied here, the correlation between theory and experiment is better for the aeroelastic model, which uses the high-fidelity (ANSYS) structural model. Both flutter velocity and frequency as well as the LCO amplitudes and frequencies that are predicted using the higher-fidelity stuctural model correlate well with experiment. In particular the flutter and LCO results predicted using the high-fidelity structural model are similar, both qualitatively and quantitatively, for the two different in-plane boundary conditions. However the results obtained from the von Karman model differ substantially for the two different in-plane boundary conditions.

In Brief Although aspirin has been empirically used to prevent cardiovascular disease since the 1940s, there remains disagreement regarding the specific use of aspirin in people with diabetes. Despite this disagreement, several organizations have provided guidelines and recommendations concerning patient selection when considering aspirin use for this purpose. This review provides a brief overview of currently available recommendations related to aspirin use in the prevention of cardiovascular events in people with and without diabetes.

Home blood pressure monitoring (HBPM) may be useful in the management of many patients with hypertension and diabetes. Blood pressure monitoring traditionally has been carried out in providers’ offices. However, many patients visit their providers only once or twice a year, which limits their ability to monitor hypertension. Over the past several years, HBPM technology has evolved to a point where accuracy and ease of use now make this form of monitoring feasible and useful in many cases. This evolution has been similar in some ways to that of blood glucose meters. When relatively accurate and easy to use blood glucose monitors were first produced, their role was a subject of debate. Today, they are widely accepted as a standard part of care. Whether HBPM will follow a similar course remains to be seen. This article provides a brief overview of methods of blood pressure measurement, recommendations from expert groups on the use of this technology, potential benefits and problems, and a review of some of the more useful devices. Individuals with diabetes are at great risk for cardiovascular disease. Part of this increased risk is because of hypertension. There is a very high incidence of hypertension in patients with diabetes. One survey estimated that 54.8% of Caucasians, 60.4% of African Americans, and 65.3% of Mexican Americans who had diabetes also had hypertension.1 Several trials have also demonstrated the importance of blood pressure–lowering in hypertensive patients with diabetes. Two of the most significant of these trials were the United Kingdom Prospective Diabetes Study (UKPDS) and the Hypertension Optimal Treatment (HOT) study. The HOT study reported a 51% reduction in cardiac events in the diabetes subpopulation ( n = 1,501) who were randomized to the more intensive blood pressure arm (goal: diastolic blood pressure of 80 vs. 90 mmHg).2 The …

Our ability to gain strict glycemic control in diabetes has improved with the introduction of novel insulins. New formulations, novel insulin molecules, and various methods of insulin delivery are able to more closely approximate the normal physiologic insulin response than conventional preparations. In this article, the authors review the development of insulin formulations and the pharmacology of currently available insulin molecules and those soon to be on the market.

To examine the significance of chemokine activation of CXCR2 in wound healing after chemical burn, cutaneous injury was created by topical application of nitrogen mustard on CXCR2 wild type (+/+), heterozygous (+/−), and knockout (−/−) mice. Wounds were analyzed histologically for neutrophil and monocyte infiltration and for reepithelialization at postwound days 4, 7, and 10. Neutrophil recruitment to the wound site was reduced through postwound day 7 in CXCR2 −/− mice as indicated by myeloperoxidase assay and by visual quantitation. Because there is always concern that mice with targeted deletion of a specific receptor may undergo developmental adaptations to offset the loss of the receptor, we also accessed chemical wound repair in the presence of a small molecule antagonist of CXCR2. Dietary supplementation with a CXCR2 antagonist (SB-265610) during the wound repair process also markedly delayed healing parameters in CXCR2 +/+ mice, even greater than treatment with glucocorticoids. These parallel studies further establish that mice deficient in CXCR2 function exhibit delayed cutaneous wound healing that may be primarily linked to impaired neutrophil recruitment after chemical burn with nitrogen mustard. Thus, there may be a potential therapeutic benefit of treating nitrogen mustard-induced skin lesions with agonists of CXCR2 to facilitate the wound repair process.

In Brief The prevalence of type 2 diabetes has been increasing rapidly and with it has been resultant morbidity and mortality. Strict glycemic control reduces the progression of diabetic microvascular disease; however, most patients treated with sulfonylureas require additional insulin therapy. This article addresses common clinician concerns about prescribing insulin early in type 2 diabetes. It presents strategies for incorporating basal insulin therapy with glargine (Lantus) into a regimen that promotes compliance.

Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S, Menne J, Mimran A, Rabelink TJ, Ritz E, Ruilope LM, Rump LC, Viberti G, for the ROADMAP Trial Investigators: Olmesartan for delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 364:907–917, 2011 Objective. Microalbuminuria is a predictor of cardiovascular disease (CVD), as well as diabetes-related nephropathy. This study was designed to determine whether the occurrence of microalbuminuria could be prevented or delayed in patients with type 2 diabetes with the angiotensin receptor blocker (ARB) olmesartan. Design and methods. This study was a randomized, multicenter, double-blind, controlled trial of 4,447 patients with type 2 diabetes. The patients were 18–75 years of age and had normoalbuminuria at the onset of the trial. They were randomized to receive either placebo or olmesartan, 40 mg daily, for a median of 3.2 years. During the trial, patients were treated to a blood pressure of < 130/90 mmHg using conventional antihypertensive medications (excluding ACE inhibitors, ARBs, or aldosterone blockers except for the ARB olmesartan in the active treatment group). Patients who had used ACE inhibitors or ARBs during the 6-month period leading up to the study were excluded. Blood pressure was measured with an automated device at each follow-up visit. The blood pressure value used was the mean of three measurements taken at 3-minute intervals by an automated device. The primary outcome was the elapsed time until the initial onset of microalbuminuria. Urine was tested by validated measurements of morning spot urine samples. Microalbuminuria was described in this trial as a urinary albumin (mg) to creatinine (g) ratio of > 35 in women or > 25 in men. Any new abnormal albumin-to-creatinine ratio was confirmed by another positive result (out …

Objective To review the increasingly common use of insulin therapy in patients with type 2 diabetes and the practical aspects of initiating insulin therapy in these patients. Data Sources Recent scientific and clinical literature identified through MEDLINE searches for the years 1995-2001 using the terms oral agents, type 2 diabetes, insulin therapy, glycemic control and diabetic complications, glucose toxicity, insulin lispro, insulin aspart, and insulin glargine. Study Selection Reports of key large (1,000 patients or more) and significant smaller, randomized, controlled clinical trials were reviewed. For studies comparing insulin analogs, the authors reviewed a sampling of the identified trials for their characteristics and clinical importance Data Synthesis Tight blood glucose control can help reduce the risk of diabetes complications. Evidence suggests that early insulin therapy can help correct the underlying pathogenetic abnormalities in type 2 diabetes and improve long-term glycemic control. For these reasons, some diabetes experts advocate the initiation of insulin therapy earlier in the course of type 2 diabetes than has been common in the past. Insulin regimens should be designed to mimic the body's natural physiologic secretion of insulin, including the basal amounts released continuously by the pancreas and the insulin surges produced in response to glucose loads. Using new insulin analogs is a useful approach to achieving this ideal. Insulin glargine provides a nearly constant, peakless release of insulin when injected subcutaneously once daily. Two new rapid-acting insulin analogs, insulin lispro (Humalog—Lilly) and insulin aspart (NovoLog—Novo Nordisk), enhance patients' flexibility in terms of meals by permitting injection immediately before meals, rather than 30 minutes before meals, as with regular insulin Conclusion Patients should be reassured that early initiation of insulin therapy is a positive event that should improve their long-term health and does not represent a decline in the course of their disease

OBJECTIVE: To review the pharmacology, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical efficacy of insulin glargine. DATA SOURCES: Primary and review articles regarding insulin glargine were identified by MEDLINE search (1966–July 2001); abstracts were identified through Institute for Scientific Information Web of Science (1995–July 2001) and the American Diabetes Association. Additional information was obtained from the insulin glargine product information. STUDY SELECTION AND DATA EXTRACTION: All of the articles and meeting abstracts identified from the data sources were evaluated, and all information deemed relevant was included in this review. Priority was placed on data from the primary medical literature. DATA SYNTHESIS: Insulin glargine is a long-acting, recombinant human insulin analog that is given once daily as a basal source of insulin in patients with type 1 or type 2 diabetes mellitus. Modification of the basic insulin structure has produced a new insulin that is soluble at an acidic pH, but precipitates in the subcutaneous tissue and is slowly released from a depot. Insulin glargine has a slower onset of action than NPH insulin and a longer duration of action with no peak activity. Once-daily administration of insulin glargine has comparable efficacy to that of NPH insulin administered once or twice daily in basal-bolus regimens when used in combination with intermittent doses of regular insulin or insulin lispro in patients with type 1 and type 2 diabetes, and in conjunction with oral antidiabetic agents in patients with type 2 diabetes. Overall, insulin glargine has an incidence of hypoglycemia comparable to or less than that of NPH insulin, with a reduced incidence of nocturnal hypoglycemia compared with NPH insulin seen in some studies. CONCLUSIONS: Insulin glargine is a long-acting insulin analog capable of providing 24-hour basal insulin coverage when administered once daily at bedtime. Its activity profile, which lacks a pronounced peak, more closely resembles that of endogenous basal insulin than that of other intermediate- or long-acting insulins and appears more likely to be associated with a reduced incidence of hypoglycemia, particularly nocturnal hypoglycemia. Insulin glargine physiologically provides basal insulin but, for most patients, the addition of a rapid-acting insulin, like insulin lispro, before or with meals will need to be included in the treatment regimen to achieve optimal management of blood glucose concentrations.

Although aspirin is one of our oldest pharmacological agents and much is known about it, our understanding of the particulars of its use as a preventive measure for cardiovascular disease (CVD) still resides in the domain of debate. Clearly, aspirin does offer some benefit in reducing the risk of CVD, but questions remain regarding the choice of patients and the optimal dose. Patients with diabetes comprise a special population and are often prescribed aspirin for its potential cardiovascular risk-reductive action. This brief article reviews the use of aspirin in this population as a primary preventive measure. It focuses on several recently released position statements, including one recently co-issued by the American Diabetes Association (ADA), the American Heart Association (AHA), and the American College of Cardiology Foundation (ACCF). Salicin, a natural precursor of aspirin found in willow bark and leaves, was used during the time of Hippocrates (400 BC) for the attenuation of pain and as an anti-pyretic.1 In the 1800s, aspirin was synthesized from the spirea plant (which is rich in salicin), and by 1899, the Bayer pharmaceutical company was distributing aspirin to physicians for use in their patients. Aspirin was typically used for the management of pain, fever, and inflammation, but in 1948, Dr. Lawrence Craven, using only his intuition and empirical observations, noted that his patients treated with aspirin did not suffer heart attacks. Based on this notion, he routinely prescribed aspirin to his patients as a preventive measure.2 Ironically, in 1957, Craven died at the age of 74 of a myocardial infarction (MI), while denying himself aspirin therapy because he fell out of the age range that he felt benefited from treatment (45–65 years). It is interesting to note that his initial recommendations were fairly consistent with today's data-based recommendations. The elucidation of aspirin's mechanisms …

In Brief This article provides an overview of the development of insulins, oral agents, and noninsulin injectable agents used in the management of hyperglycemia in patients with diabetes. It also briefly reviews the pharmacological impact and salient side effects of these medications.

IN BRIEF The pharmacological management of type 2 diabetes has changed dramatically in the past few years with the introduction of many new medications, including α-glucosidase inhibitors, a biguanide, the thiazolidinediones, insulin analogs, meglitinides, and d-phenylalanine derivatives. These new agents have dramatically increased the number of options available to providers and patients. Combination therapy has become commonplace for the management of hyperglycemia in patients with type 2 diabetes. This article briefly reviews some of the more recent pharmacological advances in diabetes care.

In BriefVarious methods of insulin administration other than injection have been sought since the discovery of insulin. For the past several years, systems that deliver insulin via the pulmonary route have been developed and evaluated. Based on available data, pulmonary insulin appears to be safe, efficacious, and well accepted by patients. This article describes the technology behind several of these pulmonary administration systems and outlines the most recent data from clinical trials evaluating pulmonary insulin.

Ironically, pharmacotherapy can harm the very patients it is intended to help if clinically significant drug interactions occur. However, knowledge of the role of the hepatic cytochrome P-450 isoenzyme system in drug interactions has expanded greatly with advances in gene-mapping technologies, and an understanding of the system can aid physicians in preventing or minimizing complications from drug interactions mediated through that system. The authors summarize the role of important isoenzymes and drugs that induce and inhibit the P-450 system. They also discuss serious drug interactions mediated through the P-450 system and ways to predict and avoid them. As a special aid, they provide a reference guide which, when used faithfully in prescribing, should result in better drug therapy.

To compare the effect of the addition of regular insulin as a premixed 70/30 insulin to the treatment regimen of patients with type 2 diabetes who had used NPH insulin alone relative to overall glycemic control (postprandial blood glucose), patient satisfaction, and health-related quality of life.We studied 90 patients with type 2 diabetes in a 10-week, randomized, double-blind, crossover trial involving 9 clinical investigators. Patients previously treated with NPH insulin alone were transferred to 30% regular insulin added to 70% NPH as a premixed insulin (70/30) administered twice daily. Patients in one sequence group received NPH insulin twice daily for 4 weeks followed by 70/30 insulin for 4 weeks; in the second sequence group, the order was reversed.The magnitude of the 1.5- and 2-hour postprandial glucose excursion was reduced with 70/30 insulin in comparison with NPH insulin, and patients treated with 70/30 insulin experienced fewer hypoglycemic events than with NPH insulin. With regard to health-related quality of life, patients treated with 70/30 insulin rated their physical functioning as better; rated their ability to be spontaneous, follow the meal plan, and interact socially to be less difficult; and had less fear of hypoglycemia and perceived their diabetes to be better controlled than when treated with NPH insulin alone.In patients with type 2 diabetes mellitus, premixed 70/30 insulin improved postprandial glycemic control and health-related quality of life without increasing the frequency of hypoglycemic events and without any additional cost.

Diabetic nephropathy is one of the leading causes of end-stage renal disease. Because of this, a significant proportion of patients requiring renal transplantation also have diabetes. Combination renal and pancreas transplant has been shown to be beneficial in some patients with insulin-dependent (type I) diabetes mellitus, but this finding is not consistent in all studies. Strict glycaemic control in the post-transplant patient has been shown to reduce expansion of the mesangial matrix in the glomeruli and, when considered in the context of the Diabetes Control and Complications Trial, strongly suggests that reasonable glycaemic control in the post-transplant patient will improve outcome. A myriad of post-transplant regimens are used; however, almost all regimens will present problems that are of concern in the patient with diabetes. Lastly, post-transplant glycaemic control must be individualised based on the patient's particular characteristics.