Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation: A Randomized Clinical Trial.

Importance: Lipoprotein(a) (Lp[a]) is associated with atherosclerotic disease and aortic stenosis. Lp(a) forms by bonding between apolipoprotein(a) (apo[a]) and apo B100. Muvalaplin is an orally administered small molecule that inhibits Lp(a) formation by blocking the apo(a)-apo B100 interaction while avoiding interaction with a homologous protein, plasminogen.

The Efficacy, Safety, and Pharmacology of a Ghrelin O-Acyltransferase Inhibitor for the Treatment of Prader-Willi Syndrome.

Context: Acylated ghrelin (AG) stimulates appetite and is elevated compared to its unacylated (UAG) counterpart in Prader-Willi syndrome (PWS). GLWL-01 is a selective, reversible inhibitor of ghrelin O-acyltransferase (GOAT), the enzyme that converts UAG into AG.

Objective: This work aimed to assess the efficacy, pharmacokinetics, pharmacodynamics, and safety of GLWL-01 in the treatment of PWS patients.

Glucagon Administration by Nasal and Intramuscular Routes in Adults With Type 1 Diabetes During Insulin-Induced Hypoglycaemia: A Randomised, Open-Label, Crossover Study.

Introduction: Many commercially available glucagon products for treatment of severe hypoglycaemia require cumbersome reconstitution and potentially intimidating injection during an emergency. Nasal glucagon (NG) is a novel drug-device combination product consisting of a single-use dosing device that delivers glucagon dry powder through nasal administration. The present study assessed whether 3 mg NG was non-inferior to 1 mg intramuscular glucagon (IMG) in adults with type 1 diabetes.

NASAL GLUCAGON DELIVERY IS MORE SUCCESSFUL THAN INJECTABLE DELIVERY: A SIMULATED SEVERE HYPOGLYCEMIA RESCUE.

A severe hypoglycemia (SH) episode is an acute, high-stress moment for the caregivers of persons with diabetes (PWD). We compared the success rates of nasal glucagon (NG) and injectable glucagon (IG) administration for PWD-trained and untrained users in treating simulated SH episodes. Thirty-two PWD-trained users and 33 untrained users administered NG and IG to high-fidelity manikins simulating treatment of an SH emergency.

Evaluation of the effects of an oral notch inhibitor, crenigacestat (LY3039478), on QT interval, and bioavailability studies conducted in healthy subjects.

Purpose: Crenigacestat (LY3039478) is a Notch inhibitor currently being investigated in advanced cancer patients. Conducting clinical pharmacology studies in healthy subjects avoids nonbeneficial drug exposures in cancer patients and mitigates confounding effects of disease state and concomitant medications.

Methods: Three studies were conducted in healthy subjects, assessing safety, pharmacokinetics, effect on QT interval, and relative and absolute bioavailability of crenigacestat.

Serum Lipid and Protein Changes in Healthy Dyslipidemic Subjects Given a Selective Inhibitor of p70 S6 Kinase-1.

The safety, pharmacokinetic, and pharmacodynamic effects of LY2584702, a selective inhibitor for p70 S6 serine/threonine protein kinase-1, were evaluated in healthy dyslipidemic volunteers. LY2584702 was tolerated well as a monotherapy and dose-dependently reduced low-density lipoprotein cholesterol and triglycerides by up to 60% and 50%, respectively, without significantly changing high-density lipoprotein cholesterol levels in plasma. LY2584702 also dose-dependently decreased factor V activity.

Impact of Increased Gastric pH on the Pharmacokinetics of Evacetrapib in Healthy Subjects.

Study Objective: To examine the effect of increased gastric pH on exposure to evacetrapib, a cholesteryl ester transfer protein inhibitor evaluated for the treatment of atherosclerotic heart disease.

Design: Open-label, two-treatment, two-period, fixed-sequence crossover study.

Setting: Clinical research unit.

Effect of hepatic or renal impairment on the pharmacokinetics of evacetrapib.

Purpose: The aim of this study is to investigate the effect of hepatic or renal impairment on the pharmacokinetics of a single 130-mg evacetrapib dose.

Methods: Two open-label, parallel-design studies in males and females with normal hepatic function or Child-Pugh mild, moderate, or severe hepatic impairment, or with normal renal function or severe renal impairment. Non-compartmental pharmacokinetic parameters were estimated from plasma concentration-time data.

Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [(13) C8 ]-evacetrapib as a tracer.

This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130-mg evacetrapib oral dose and 4-h intravenous (IV) infusion of 175 µg [(13) C8 ]-evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [(13) C8 ]-evacetrapib using high-performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration-time curve (AUC) from zero to infinity (AUC[0-∞]) and to the last measureable concentration (AUC[0-tlast ]), were calculated.

Evacetrapib: in vitro and clinical disposition, metabolism, excretion, and assessment of drug interaction potential with strong CYP3A and CYP2C8 inhibitors.

Evacetrapib is an investigational cholesteryl ester transfer protein inhibitor (CETPi) for reduction of risk of major adverse cardiovascular events in patients with high-risk vascular disease. Understanding evacetrapib disposition, metabolism, and the potential for drug-drug interactions (DDI) may help guide prescribing recommendations. In vitro, evacetrapib metabolism was investigated with a panel of human recombinant cytochromes P450 (CYP).

CYP-mediated drug-drug interactions with evacetrapib, an investigational CETP inhibitor: in vitro prediction and clinical outcome.

Aims: Evacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor under development for reducing cardiovascular events in patients with high risk vascular disease. CETP inhibitors are likely to be utilized as 'add-on' therapy to statins in patients receiving concomitant medications, so the potential for evacetrapib to cause clinically important drug-drug interactions (DDIs) with cytochromes P450 (CYP) was evaluated.

Methods: The DDI potential of evacetrapib was investigated in vitro, followed by predictions to determine clinical relevance.

A Multidose Study to Examine the Effect of Food on Evacetrapib Exposure at Steady State.

Purpose: To determine the effect of a high-fat meal on evacetrapib exposure at steady state in healthy participants.

Methods: This was a randomized, 2-period, 2-sequence, open-label, crossover study. Patients were randomly assigned to 1 of the 2 treatment sequences in which they received evacetrapib 130 mg/d for 10 days following a 10-hour fast each day or following a high-fat breakfast each day.

Determining pharmacological selectivity of the kappa opioid receptor antagonist LY2456302 using pupillometry as a translational biomarker in rat and human.

Background: Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappa opioid receptor antagonist, LY2456302, exhibits ~30-fold higher affinity for kappa opioid receptors over mu opioid receptors, which is the next closest identified pharmacology.

Methods: Here, we determined kappa opioid receptor pharmacological selectivity of LY2456302 by assessing mu opioid receptor antagonism using translational pupillometry in rats and humans.

Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults.

Objectives: We investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of evacetrapib.

Methods: Healthy volunteers received multiple daily doses of evacetrapib (10-600 mg) administered for up to 15 days in a placebo-controlled study.

Key Findings: Mean peak plasma concentrations of evacetrapib occurred at 4-6 h and terminal half-life ranged 24-44 h.

Evacetrapib at a supratherapeutic steady state concentration does not prolong QT in a thorough QT/QTc study in healthy participants.

Purpose: To evaluate whether evacetrapib prolongs QT intervals in healthy participants.

Methods: This was a single-center, randomized, active and placebo-controlled, 3-period, 6-sequence, and crossover study. Participants were randomized to 1 of 6 treatment sequences in which they received 1 of 3 treatments: evacetrapib 1200 mg daily for 10 days (supratherapeutic dose), moxifloxacin 400 mg for 1 day (positive control), or placebo for 10 days in each of the 3 separate treatment periods.

LOINC, a universal standard for identifying laboratory observations: a 5-year update.

The Logical Observation Identifier Names and Codes (LOINC) database provides a universal code system for reporting laboratory and other clinical observations. Its purpose is to identify observations in electronic messages such as Health Level Seven (HL7) observation messages, so that when hospitals, health maintenance organizations, pharmaceutical manufacturers, researchers, and public health departments receive such messages from multiple sources, they can automatically file the results in the right slots of their medical records, research, and/or public health systems. For each observation, the database includes a code (of which 25 000 are laboratory test observations), a long formal name, a "short" 30-character name, and synonyms.

Electronic laboratory reporting: barriers, solutions and findings.

Electronic laboratory reporting can improve surveillance for notifiable conditions. Building on standards for message structure and content, we have implemented an electronic laboratory reporting system by building on the infrastructure created for the Indiana Network for Patient Care (INPC). The system has proven reliable in delivering results and scalable to multiple laboratories over 36 months of use.

The regenstrief medical record system 2000:Expanding the breadth and depth of a community wide EMR.

The Regenstrief Medical Record System (RMRS) continues to grow in breadth and depth. As we expand its breadth -- the system links 5 health care systems, 11 acute care hospitals, 13 homeless care sites, nearly 100 clinics/offices and the county and state health departments -- we have had to overcome critical problems inherent to creating a community wide electronic medical record (EMR). Data for more than 2 million patients consisting of 300 million coded observations, 5.

The Regenstrief Medical Record System: a quarter century experience.

Entrusted with the records for more than 1.5 million patients, the Regenstrief Medical Record System (RMRS) has evolved into a fast and comprehensive data repository used extensively at three hospitals on the Indiana University Medical Center campus and more than 30 Indianapolis clinics. The RMRS routinely captures laboratory results, narrative reports, orders, medications, radiology reports, registration information, nursing assessments, vital signs, EKGs and other clinical data.

Units of measure in clinical information systems.

The authors surveyed existing standard codes for units of measures, such as ISO 2955, ANSI X3.50, and Health Level 7's ISO+. Because these standards specify only the character representation of units, the authors developed a semantic model for units based on dimensional analysis.

Canopy computing: using the Web in clinical practice.

The rain forest canopy is a seamless web through which arboreal creatures efficiently move to reach the edible fruits without any attention to the individual trees. Individual health care computer systems are rich with patient data, but rather than a canopy linking all the trees in the forest, the data "fruit" come from a diverse forest of individual computer "trees"-laboratory systems, word processing systems, pharmacy systems, and the like. These different sources of patient information are difficult or impossible to reach by individual physicians, especially from their offices.

Behaviors predicting foot lesions in patients with non-insulin-dependent diabetes mellitus.

Associations between specific foot-care behaviors and foot lesions in patients with non-insulin-dependent diabetes mellitus were prospectively investigated. Data from a randomized controlled trial for preventing diabetic foot lesions were analyzed as a prospective cohort using logistic regression. Independent variables included foot-care behaviors, patient self-foot examination, going barefoot, availability of foot-care assistance, and visits to health-care providers.

What is done, what is needed and what is realistic to expect from medical informatics standards.

Medical informatic experts have made considerable progress in the development of standards for orders and clinical results (CEN, HL7, ASTM), EKG tracings (CEN), diagnostic images (DICOM), claims processing (X12 and EDIFAC) and in vocabulary and codes (SNOMED, Read Codes, the MED, LOINC). Considerable work still remains to be carried out. Abstract models of health care information have to be created, to cover the necessary domain, and yet be simple enough to assimilate, implement, and manage.

Informatics Workup.

We introduce the concept of a Medical Informatics Workup performed by fourth year medical students working in a busy inner-city Emergency Room. These students use portable computers (Macintosh PowerBook 170s connected to a removable cartridge hard drive and CD-ROM drive) to do the patient workups. The PowerBook 170 contains the automated medical record entry software (IMR-E), five expert system software packages, and a program that allows the PowerBook to emulate a PC-compatible computer.