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Standard practice to minimize variability in beta cell function (BCF) measurement is to test in inpatient (IP) settings. IP testing strains trial subjects, investigators, and budgets. Outpatient (OP) testing may be a solution although there are few reports on OP BCF testing variability. We compared variability metrics between OP and IP from a standardized mixed meal tolerance test (MMTT) and arginine stimulation test (AST) in two separate type 2 diabetes (T2DM) cohorts (OP, n = 20; IP n = 22) in test-retest design. MMTT variables included: insulin sensitivity (Si); beta cell responsivity (Φtot); and disposition index (DItot = Si* Φtot) following 470 kCal meal. AST variables included: acute insulin response to arginine (AIRarg) and during hyperglycemia (AIRargMAX). Results: Baseline characteristics were well-matched. Between and within subject variance for each parameter across cohorts, and intraclass correlation coefficients (ICC-a measure of reproducibility) across parameters were generally comparable for OP to IP. Table summarizes the ICC results for each key parameter and cohort.Test/ParameterOutpatient (95% CI)Inpatient (95% CI)MMTT: Si0.49(0,0.69)0.28(0,0.60)MMTT: Φtot0.65(0.16,0.89)0.81(0.44,0.93)MMTT: DI0.67(0,0.83)0.36(0,0.69)AST: AIR Arg0.96(0.88,0.98)0.84(0.59,0.94)AST: AIR Arg Max0.97(0.90,0.99)0.95(0.86,0.97)AST: ISR0.93(0.77,0.97)0.93(0.82,0.96)In conclusion, the variability (reproducibility) of BCF measures from standardized MMTT and AST is comparable between OP and IP settings. These observations have significant implications for complexity and cost of metabolic studies.

This randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes.Patients (N = 116) discontinued their antihyperglycemic medications 2 weeks before randomization. Patients received canagliflozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily, or placebo at 2 study centers in the United States and Germany, or canagliflozin 30 mg once daily or placebo at 1 study center in Korea, while maintaining an isocaloric diet for 2 weeks. On Days -1, 1, and 16, urinary glucose excretion (UGE), plasma glucose (PG), fasting PG (FPG), and insulin were measured. The renal threshold for glucose (RTG) was calculated from UGE, PG, and estimated glomerular filtration rate. Safety was evaluated based on adverse event (AE) reports, vital signs, electrocardiograms, clinical laboratory tests, and physical examinations.Canagliflozin increased UGE dose-dependently (∼80-120 g/day with canagliflozin ≥100 mg), with increases maintained over the 14-day dosing period with each dose. Canagliflozin dose-dependently decreased RTG, with maximal reductions to ∼4-5 mM (72-90 mg/dL). Canagliflozin also reduced FPG and 24-hour mean PG; glucose reductions were seen on Day 1 and maintained over 2 weeks. Plasma insulin reductions with canagliflozin were consistent with observed PG reductions. Canagliflozin also reduced body weight. AEs were transient, mild to moderate in intensity, and balanced across groups; 1 canagliflozin-treated female reported an episode of vaginal candidiasis. Canagliflozin did not cause hypoglycemia, consistent with the RTG values remaining above the hypoglycemia threshold. At Day 16, there were no clinically meaningful changes in urine volume, urine electrolyte excretion, renal function, or routine laboratory test values.Canagliflozin increased UGE and decreased RTG, leading to reductions in PG, insulin, and body weight, and was generally well tolerated in patients with type 2 diabetes.ClinicalTrials.gov NCT00963768.

CC‐90001 selectively inhibits c‐Jun N‐terminal kinase (JNK), a stress‐activated protein implicated in fibrosis. In 3 phase 1 trials evaluating CC‐90001 pharmacokinetics, pharmacodynamics, and safety, healthy adults (N = 184) received oral CC‐90001 in a single dose (10–720 mg) or multiple doses (30–480 mg once daily for 7–18 days) or placebo. CC‐90001 was rapidly absorbed (median time to maximum concentration, 1–4 hours) and eliminated with a mean terminal elimination half‐life of 12–28 hours. Steady state was reached on day 5, with a mean accumulation ratio of 1.5‐ to 2‐fold following daily dosing. Exposure was similar in fed versus fasted participants and in Japanese versus non‐Japanese participants. CC‐90001 demonstrated dose‐ and exposure‐dependent inhibition of JNK as determined by histopathological analysis of c‐Jun phosphorylation in ultraviolet‐irradiated skin. The most common treatment‐emergent adverse events were nausea and headache; all were mild or moderate in intensity. Based on exposure‐response analysis using high‐quality electrocardiogram data, no clinically relevant QT prolongation liability for CC‐90001 was observed. Overall, single‐ and multiple‐dose CC‐90001 were generally safe and well tolerated at the tested doses and demonstrated JNK pathway engagement. These results support further clinical evaluation of CC‐90001. [ABSTRACT FROM AUTHOR]

Introduction: Diabetes mellitus is now a leading cause of morbidity and mortality. SGLTR 2 inhibitors reduce proximal tubular glucose reabsorption and increases urinary glucose excretion. Canagliflozin is selected as the drug in this study for the treatment of control of PPG in TYPE 2 DM patients to see the effect without changing the base line medication. Objectives: To observe the effect of Canagliflozin on postprandial blood glucose in Type2 DM. Materials and Methods: Prior permission was obtained from Institutional Ethical Committee before study was undertaken in the Department of General Medicine of NRI Institute Of Medical Sciences, Sangivalasa, Visakhapatnam) on 100 patients admitted during January 2020 to December 2020. Inclusion Criteria: The study will include Type 2 DM patient of >15 yr age having elevated FPG/normal FPG with increasing PPG attended to this NRIIMS during study period. Exclusion criteria (1) Pregnancy (2) Inflammatory bowel disease, IBS (3) Chronic Kidney Disease (4) Acute or chronic disease which may cause tissue hypoxia (4) Hepatic failure. Results: Canagliflozin monotherapy is useful in the early stage Type2 DM with elevated post prandial plasma glucose. PPG results before and after therapy was of average 210 mg/dl and 130 mg/dl respectively after 24 wks. Patient on Biguanides when PPG is uncontrolled, adding Cangliflozin significantly reduced PPG in patients. Before and after therapy with Canagliflozin were on average 250 mg/dl and 146mg/dl respectively after 24 weeks. Conclusion: Canagliflozin is very effective in controlling postprandial blood glucose either as monotherapy or with combination of other OHA or with Insulin. [ABSTRACT FROM AUTHOR]

Introduction: The aims of this study were to characterize the multiple-dose pharmacokinetics (PK) of ozanimod's major active metabolites (CC112273 and CC1084037) and to evaluate the pharmacodynamic and PK interactions with pseudoephedrine (PSE). Methods: In this phase 1, single-center, randomized, double-blind, placebo-controlled study, 56 healthy adult subjects were randomized to receive either placebo or ozanimod once daily for 30 days (0.23 mg on days 1–4, 0.46 mg on days 5–7, 0.92 mg on days 8–10, and 1.84 mg on days 11–30). On day 30, a single oral dose of PSE 60 mg was co-administered with placebo or ozanimod. Maximum time-matched change in systolic blood pressure (SBP) from baseline (day 29) following PSE administration on day 30 was calculated. Plasma PK parameters for ozanimod, CC112273, CC1084037, and PSE were estimated using noncompartmental methods. Results: Fifty-two subjects (92.9%) completed the study. Following multiple dosing, approximately 94% of circulating total active drug exposure was represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%). Exposures of CC112273 and CC1084037 were highly correlated. Mean maximum time-matched change from baseline for SBP was not significantly different between ozanimod + PSE and placebo + PSE. Ozanimod also had no effect on the PK of PSE. Co-administration of ozanimod with a single dose of PSE in healthy subjects was generally well tolerated. While CC112273 and CC1084037 selectively inhibited monoamine oxidase (MAO)-B in vitro, both active metabolites do not inhibit platelet MAO-B activity in vivo. Conclusion: Concomitant administration of ozanimod with PSE, a sympathomimetic agent, did not potentiate the effects on blood pressure. Trial Registration: NCT03644576. [ABSTRACT FROM AUTHOR]

Introduction: The aims of this study were to characterize the single-dose pharmacokinetics (PK) of the major active metabolites of ozanimod, CC112273 and CC1084037, and to evaluate the effect of gemfibrozil (a strong inhibitor of cytochrome P450 [CYP] 2C8), itraconazole (a strong inhibitor of CYP3A and P-glycoprotein [P-gp]), and rifampin (a strong inducer of CYP3A/P-gp and moderate inducer of CYP2C8) on the single-dose PK of ozanimod and its major active metabolites in healthy subjects. Methods: This was a phase 1, randomized, parallel-group, open-label study with two parts. In part 1, 40 subjects were randomized to receive a single oral dose of ozanimod 0.46 mg (group A, n = 20) or oral doses of gemfibrozil 600 mg twice daily for 17 days with a single oral dose of ozanimod 0.46 mg on day 4 (group B, n = 20). In part 2, 60 subjects were randomized to receive a single oral dose of ozanimod 0.92 mg (group C, n = 20), oral doses of itraconazole 200 mg once daily for 17 days with a single oral dose of ozanimod 0.92 mg on day 4 (group D, n = 20), or oral doses of rifampin 600 mg once daily for 21 days with a single oral dose of ozanimod 0.92 mg on day 8 (group E, n = 20). Plasma PK parameters for ozanimod, CC112273, and CC1084037 were estimated using noncompartmental methods. Results: Dose-proportional increases in maximum observed concentration (Cmax) and area under the concentration–time curve (AUC) were observed for ozanimod, CC112273, and CC1084037. The mean terminal elimination half-life (t1/2) for ozanimod was approximately 20–22 h while the mean t1/2 for CC112273 and CC1084037 were approximately 10 days. CC112273 and CC1084037 exposures were highly correlated with or without interacting drugs. Itraconazole increased ozanimod AUC by approximately 13% while rifampin reduced ozanimod AUC by approximately 24%, suggesting a minor role of CYP3A and P-gp in the overall disposition of ozanimod. Gemfibrozil increased the AUC for CC112273 and CC1084037 by approximately 47% and 69%, respectively. Rifampin reduced the AUC for CC112273 and CC1084037, primarily via CYP2C8 induction, by approximately 60% and 55%, respectively. Conclusions: Ozanimod's major active metabolites, CC112273 and CC1084037, exhibited similar single-dose PK properties and their exposures were highly correlated. CYP2C8 is one of the important enzymes in the overall disposition of CC112273 and subsequently its direct metabolite CC1084037. Trial Registration: Clinical trial: NCT03624959 [ABSTRACT FROM AUTHOR]

Aim: To evaluate the impact of the sodium glucose co‐transporter 2 inhibitor canagliflozin on intrahepatic triglyceride (IHTG) accumulation and its relationship to changes in body weight and glucose metabolism. Materials and methods: In this double‐blind, parallel‐group, placebo‐controlled, 24‐week trial subjects with inadequately controlled type 2 diabetes mellitus (T2DM; HbA1c = 7.7% ± 0.7%) from two centres were randomly assigned (1:1) to canagliflozin 300 mg or placebo. We measured IHTG by proton‐magnetic resonance spectroscopy (primary outcome), hepatic/muscle/adipose tissue insulin sensitivity during a 2‐step euglycaemic insulin clamp, and beta‐cell function during a mixed meal tolerance test. Analyses were per protocol. Results: Between 8 September 2014‐13 June 2016, 56 patients were enrolled. Canagliflozin reduced HbA1c (placebo‐subtracted change: −0.71% [−1.08; −0.33]) and body weight (−3.4% [−5.4; −1.4]; both P ≤ 0.001). A numerically larger absolute decrease in IHTG occurred with canagliflozin (−4.6% [−6.4; −2.7]) versus placebo (−2.4% [−4.2; −0.6]; P = 0.09). In patients with non‐alcoholic fatty liver disease (n = 37), the decrease in IHTG was −6.9% (−9.5; −4.2) versus −3.8% (−6.3; −1.3; P = 0.05), and strongly correlated with the magnitude of weight loss (r = 0.69, P < 0.001). Body weight loss ≥5% with a ≥30% relative reduction in IHTG occurred more often with canagliflozin (38% vs. 7%, P = 0.009). Hepatic insulin sensitivity improved with canagliflozin (P < 0.01), but not muscle or adipose tissue insulin sensitivity. Beta‐cell glucose sensitivity, insulin clearance, and disposition index improved more with canagliflozin (P < 0.05). Conclusions: Canagliflozin improves hepatic insulin sensitivity and insulin secretion and clearance in patients with T2DM. IHTG decreases in proportion to the magnitude of body weight loss, which tended to be greater and occur more often with canagliflozin. [ABSTRACT FROM AUTHOR]

Aims JNJ-64179375 (hereafter JNJ-9375) is a first-in-class, highly specific, large molecule, exosite 1 thrombin inhibitor. In preclinical studies, JNJ-9375 demonstrated robust antithrombotic protection with a wider therapeutic index when compared to apixaban. The purpose of the present study was to examine for the first time the antiplatelet, anticoagulant and antithrombotic effects of JNJ-9375 in a translational model of ex vivo human thrombosis. Methods and results Fifteen healthy volunteers participated in a double-blind randomized crossover study of JNJ-9375 (2.5, 25, and 250 μg/mL), bivalirudin (6 μg/mL; positive control), and matched placebo. Coagulation, platelet activation, and thrombus formation were determined using coagulation assays, flow cytometry, and an ex vivo perfusion chamber, respectively. JNJ-9375 caused concentration-dependent prolongation of all measures of blood coagulation (prothrombin time, activated partial thromboplastin time, and thrombin time; P  < 0.001 for all) and agonist selective inhibition of thrombin (0.1 U/mL) stimulated platelet p-selectin expression (P  < 0.001) and platelet-monocyte aggregates (P  = 0.002). Compared to placebo, JNJ-9375 (250 μg/mL) reduced mean total thrombus area by 41.1% (95% confidence intervals 22.3 to 55.3%; P  < 0.001) at low shear and 32.3% (4.9 to 51.8%; P  = 0.025) at high shear. Under both shear conditions, there was a dose-dependent decrease in fibrin-rich thrombus (P  < 0.001 for both) but not platelet-rich thrombus (P  = ns for both). Conclusion Exosite 1 inhibition with JNJ-9375 caused prolongation of blood coagulation, selective inhibition of thrombin-mediated platelet activation, and reductions in ex vivo thrombosis driven by a decrease in fibrin-rich thrombus formation. JNJ-9375 represents a novel class of anticoagulant with potential therapeutic applications. [ABSTRACT FROM AUTHOR]

Background: The aims of this study were to 1. define the responses of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, and peptide YY (PYY) to an oral meal and to intravenous L-arginine; and 2. examine correlation of enteroendocrine hormones with insulin secretion. We hypothesized a relationship between circulating incretin concentrations and insulin secretion. Methods: Subjects with normal glucose tolerance (NGT, n = 23), prediabetes (PDM, n = 17), or with type 2 diabetes (T2DM, n = 22) were studied twice, following a mixed test meal (470 kCal) (mixed meal tolerance test [MMTT]) or intravenous L-arginine (arginine maximal stimulation test [AST], 5 g). GLP-1 (total and active), PYY, GIP, glucagon, and β cell function were measured before and following each stimulus. Results: Baseline enteroendocrine hormones differed across the glucose tolerance (GT) spectrum, T2DM generally >NGT and PDM. In response to MMTT, total and active GLP-1, GIP, glucagon, and PYY increased in all populations. The incremental area-under-the-curve (0–120 min) of analytes like total GLP-1 were often higher in T2DM compared with NGT and PDM (35–51%; P < 0.05). At baseline glucose, L-arginine increased total and active GLP-1 and glucagon concentrations in all GT populations (all P < 0.05). As expected, the MMTT and AST provoked differential glucose, insulin, and C-peptide responses across GT populations. Baseline or stimulated enteroendocrine hormone concentrations did not consistently correlate with either measure of β cell function. Conclusions/interpretation: Both MMTT and AST resulted in insulin and enteroendocrine hormone responses across GT populations without consistent correlation between release of incretins and insulin, which is in line with other published research. If a defect is in the enteroendocrine/β cell axis, it is probably reduced response to rather than diminished secretion of enteroendocrine hormones. [ABSTRACT FROM AUTHOR]

A key aspect of research into the prevention and treatment of type 2 diabetes is the availability of reproducible clinical research methodology to assess β-cell function. One commonly used method employs nonglycemic secretagogues like arginine (arg) or glucagon (glgn). This study was designed to quantify the insulin response to arg and glgn and determine test repeatability and tolerability. Obese overnight-fasted subjects with normal glucose tolerance were studied on 4 separate days: twice using arg (5 g iv) and twice with glgn (1 mg iv). Pre- and postinfusion samples for plasma glucose, insulin, and C-peptide were acquired. Arg and glgn challenges were repeated in the last 10 min of a 60-min glucose (900 mg/min) infusion. Insulin and C-peptide secretory responses were estimated under baseline fasting glucose conditions (AIRarg and AIRglgn) and hyperglycemic (AIRargMAX AIRglgnMAX) states. Relative repeatability was estimated by intraclass correlation coefficient (ICC). Twenty-three (12 men and 11 women) subjects were studied (age: 42.4 ± 8.3 yr; BMI: 31.4 ± 2.8 kg/m(2)). Geometric means (95% CI) for baseline-adjusted values AIRarg and AIRglgn were 84 (75-95) and 102 (90-115) μU/ml, respectively. After the glucose infusion, AIRargMAX and AIRglgnMAX were 395 (335-466) and 483 (355-658) μU/ml, respectively. ICC values were >0.90 for AIRarg andAIRargMAX. Glucagon ICCs were 0.83, 0.34, and 0.36, respectively, although the exclusion of one outlier increased the latter two values (to 0.84 and 0.86). Both glgn and arg induced mild adverse events that were transient. Glucagon, but not arginine, induced moderate adverse events due to nausea. Taken together, arginine is preferred to glucagon for assessment of β-cell function. [ABSTRACT FROM AUTHOR]

Introduction: This randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes. Methods: Patients (N = 116) discontinued their antihyperglycemic medications 2 weeks before randomization. Patients received canagliflozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily, or placebo at 2 study centers in the United States and Germany, or canagliflozin 30 mg once daily or placebo at 1 study center in Korea, while maintaining an isocaloric diet for 2 weeks. On Days –1, 1, and 16, urinary glucose excretion (UGE), plasma glucose (PG), fasting PG (FPG), and insulin were measured. The renal threshold for glucose (RTG) was calculated from UGE, PG, and estimated glomerular filtration rate. Safety was evaluated based on adverse event (AE) reports, vital signs, electrocardiograms, clinical laboratory tests, and physical examinations. Results: Canagliflozin increased UGE dose-dependently (∼80–120 g/day with canagliflozin ≥100 mg), with increases maintained over the 14-day dosing period with each dose. Canagliflozin dose-dependently decreased RTG, with maximal reductions to ∼4–5 mM (72–90 mg/dL). Canagliflozin also reduced FPG and 24-hour mean PG; glucose reductions were seen on Day 1 and maintained over 2 weeks. Plasma insulin reductions with canagliflozin were consistent with observed PG reductions. Canagliflozin also reduced body weight. AEs were transient, mild to moderate in intensity, and balanced across groups; 1 canagliflozin-treated female reported an episode of vaginal candidiasis. Canagliflozin did not cause hypoglycemia, consistent with the RTG values remaining above the hypoglycemia threshold. At Day 16, there were no clinically meaningful changes in urine volume, urine electrolyte excretion, renal function, or routine laboratory test values. Conclusions: Canagliflozin increased UGE and decreased RTG, leading to reductions in PG, insulin, and body weight, and was generally well tolerated in patients with type 2 diabetes. Trial Registration: ClinicalTrials.gov NCT00963768 [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor, is also a low-potency SGLT1 inhibitor. This study tested the hypothesis that intestinal canagliflozin levels postdose are sufficiently high to transiently inhibit intestinal SGLT1, thereby delaying intestinal glucose absorption. RESEARCH DESIGN AND METHODS -- This two-period, crossover study evaluated d effects of canagliflozin on intestinal glucose absorption in 20 healthy subjects using a dual-tracer method. Placebo or canagliflozin 300 mg was given 20 min before a 600-kcal mixed-meal tolerance test. Plasma glucose, ³H-glucose, 14C-glucose, and insulin were measured frequently for 6 h to calculate rates of appearance of oral glucose (RaO) in plasma, endogenous glucose production, and glucose disposal. RESULTS -- Compared with placebo, canagliflozin treatment reduced postprandial plasma d ? glucose and insulin excursions (incremental 0- to 2-h area under the curve [AUC0-2h] reductions of 35% and 43%, respectively; P < 0.001 for both), increased 0- to 6-h urinary glucose excretion (UGE0-6h, 18.2 ± 5.6 vs.,0.2 g; < P < 0.001), and delayed RaO. Canagliflozin reduced AUC RaO by 31% over 0 to 1 h (geometric means, 264 vs. 381 mg/kg; P < 0.001) and by 20% over 0 to 2 h (576 vs. 723 mg/kg; P = 0.002). Over 2 to 6 h, canagliozin increased RaO such that total AUC RaO over 0 to 6 h was <6% lower versus placebo (960 vs. 1,018 mg/kg; P = 0.003). A modest (~10%) reduction in acetaminophen absorption was observed over the first 2 h, but this difference was not sufficient to explain the reduction in RaO. Total glucose disposal over 0 to 6 h was similar across groups. CONCLUSIONS -- Canagliflozin reduces postprandial plasma glucose and insulin by increasing UGE (via renal SGLT2 inhibition) and delaying RaO, likely due to intestinal SGLT1 inhibition. [ABSTRACT FROM AUTHOR]

Aims Human stresscopin is a corticotropin-releasing factor (CRF) type 2 receptor (CRFR2) selective agonist and a member of the CRF peptide family. Stimulation of CRFR2 improves cardiac output and left ventricular ejection fraction (LVEF) in patients with stable heart failure (HF) with reduced LVEF. We examined the safety, pharmacokinetics, and effects on haemodynamics and serum biomarkers of intravenous human stresscopin acetate (JNJ-39588146) in patients with stable HF with LVEF ≤35% and cardiac index (CI) ≤2.5 L/min/m2. Methods and results Sixty-two patients with HF and LVEF ≤35% were instrumented with a pulmonary artery catheter and randomly assigned (ratio 3:1) to receive an intravenous infusion of JNJ-39588146 or placebo. The main study was an ascending dose study of three doses (5, 15, and 30 ng/kg/min) of study drug or placebo administered in sequential 1 h intervals (3 h total). Statistically significant increases in CI and reduction in systemic vascular resistance (SVR) were observed with both the 15 ng/kg/min (2 h time point) and 30 ng/kg/min (3 h time point) doses of JNJ-39588146 without significant changes in heart rate (HR) or systolic blood pressure (SBP). No statistically significant reductions in pulmonary capillary wedge pressure (PCWP) were seen with any dose tested in the primary analysis, although a trend towards reduction was seen. Conclusion In HF patients with reduced LVEF and CI, ascending doses of JNJ-39588146 were associated with progressive increases in CI and reductions in SVR without significant effects on PCWP, HR, or SBP. [ABSTRACT FROM AUTHOR]

The article presents abstracts from the 72nd scientific sessions on ORALS is presented which includes a comparative analysis of three continuous glucose monitors, performance of a microdialysis-based continuous glucose monitoring (CGM) system, and transdermal continuous glucose monitoring after skin permeation.

The article presents abstracts of published studies on clinical diabetes and therapeutics that include "Burden of Sliding Scale Insulin Use in Elderly Long-Term Care Residents with Type 2 Diabetes" by Naushira Pandya, et al., "Gut Hypertrophy and L-Cell Proliferation in the Diabetic Zucker Fatty Rat" by Frederik Carl Hansen, et al., and "Sleep-Disordered Breathing Is Common in Gestational Diabetes Mellitus" by Raelene E. Maser, et al.

This section presents abstracts of papers related to diabetes including "Mild Mitochondrial Dysfunction Increases Type I Diabetic Renal and Cardiac Damage," "PDGFR-Β Deletion Improves Diabetic Nephropathy in CaM Kinase IIα (Thr286Asp) Transgenic Mice," and "Increased Axl Receptor Tyrosine Kinase and Its Ligand in Glycoxidized-LDL-Induced Mesangial Cells and Diabetic Kidney."

A list of the papers on diabetes presented from June 25 to 28, 2010 is presented including "Mild Mitochondrial Dysfunction Increases Type I Diabetic Renal and Cardiac Damage," "Is There a Link Between Elevated Serum Selenium Concentrations and Gestational Diabetes?," and "Gestational Diabetes Mellitus (GDM) May Reflect GLP-1 Resistance."

Decades of racial progress have led some researchers and policymakers to doubt that discrimination remains an important cause of economic inequality. To study contemporary discrimination, we conducted a field experiment in the low-wage labor market of New York City, recruiting white, black, and Latino job applicants who were matched on demographic characteristics and interpersonal skills. These applicants were given equivalent résumés and sent to apply in tandem for hundreds of entry-level jobs. Our results show that black applicants were half as likely as equally qualified whites to receive a callback or job offer. In fact, black and Latino applicants with clean backgrounds fared no better than white applicants just released from prison. Additional qualitative evidence from our applicants' experiences further illustrates the multiple points at which employment trajectories can be deflected by various forms of racial bias. These results point to the subtle yet systematic forms of discrimination that continue to shape employment opportunities for low-wage workers. [ABSTRACT FROM AUTHOR]

The article summarizes research on insulin secretion regulation. They include secretion in isolated cultured islets from short-chain 3-hydroxyacyl-isobutyryl-coenzyme A (CoA)-dehydrogenase (SCHAD) knockout mice to examine the mechanism of insulin dysregulation in SCHAD deficiency, potential of mammalian target of rapamycin (mTOR) inhibition as therapy for intractable hypoglycemia caused by malignant insulin secretion, and the effect of mTOR complex 1 (mTORC1) activation on mitochondrial function in pancreatic β cells.

The article presents abstracts of Eight International Symposium on Osteoporosis which include adverse dental outcomes and intravenous or oral bisphosphonates utilization in patients with osteoporosis, association between hormone therapy cessation and hip fracture risk, and the effectiveness of a Healthy Bones Program on the osteoporosis disease management.

High development costs and low success rates in bringing new medicines to the market demand more efficient and effective approaches. Identified by the FDA as a valuable prognostic tool for fulfilling such a demand, model-based drug development is a mathematical and statistical approach that constructs, validates, and utilizes disease models, drug exposure-response models, and pharmacometric models to facilitate drug development. Quantitative pharmacology is a discipline that learns and confirms the key characteristics of new molecular entities in a quantitative manner, with goal of providing explicit, reproducible, and predictive evidence for optimizing drug development plans and enabling critical decision making. Model-based drug development serves as an integral part of quantitative pharmacology. This work reviews the general concept, basic elements, and evolving role of model-based drug development in quantitative pharmacology. Two case studies are presented to illustrate how the model-based drug development approach can facilitate knowledge management and decision making during drug development. The case studies also highlight the organizational learning that comes through implementation of quantitative pharmacology as a discipline. Finally, the prospects of quantitative pharmacology as an emerging discipline are discussed. Advances in this discipline will require continued collaboration between academia, industry and regulatory agencies. [ABSTRACT FROM AUTHOR]

Purpose: The objectives of these population pharmacokinetic analyses were to (1) assess the overall disposition of pemetrexed, (2) characterize between-patient and within-patient variability and identify influential covariates with respect to pemetrexed pharmacokinetics; and, (3) provide individual empirical Bayesian estimates of pharmacokinetic parameters for use in a subsequent pharmacokinetic/pharmacodynamic evaluation of neutropenia following pemetrexed administration. Patients and methods: Data from 287 patients who received 441 cycles without folic acid or vitamin B12 supplementation during participation in one of ten phase II cancer trials were evaluated by population pharmacokinetic analysis using NONMEM. Starting doses were 500 or 600 mg pemetrexed per m2 body surface area, administered as 10-min intravenous infusions every 21 days (1 cycle). The model was developed using data from eight of the ten studies. Predictive performance was evaluated using data from the other two studies. Results: The population pharmacokinetics of pemetrexed administered as a 10-min intravenous infusion are well characterized by a two-compartment model. Typical values of total systemic clearance, central volume of distribution, distributional clearance, and peripheral volume of distribution were 91.6 ml/min, 12.9 l, 14.4 ml/min, and 3.38 l, respectively. Based on these parameter estimates, the terminal elimination half-life of pemetrexed was approximately 3.5 h. Renal function was identified as a covariate with respect to total systemic clearance, and body surface area as a covariate with respect to the central volume of distribution. Conclusion: Total systemic exposure (AUC) for a given dose of pemetrexed increases as renal function decreases. Since pharmacodynamic analyses have shown that AUC and not C max is the primary determinant of neutropenic response to pemetrexed, this suggests that dose adjustments based on renal function, rather than body surface area, might be considered for pemetrexed. [ABSTRACT FROM AUTHOR]

Purpose: The objectives of these analyses were to (1) develop a semimechanistic-physiologic population pharmacokinetic/pharmacodynamic (PK/PD) model to describe neutropenic response to pemetrexed and to (2) identify influential covariates with respect to pharmacodynamic response. Patients and methods: Data from 279 patients who received 1,136 treatment cycles without folic acid or vitamin B12 supplementation during participation in one of eight phase II cancer trials were available for analysis. Starting doses were 500 or 600 mg pemetrexed per m2 body surface area (BSA), administered as 10-min intravenous infusions every 21 days (1 cycle). The primary analyses included 105 patients (279 cycles) for which selected covariates—including vitamin deficiency marker data (i.e., homocysteine, cystathionine, methylmalonic acid, and methylcitrate [I, II, and total] plasma concentrations)—were available. Classical statistical multivariate regression analyses and a semimechanistic-physiologic population PK/PD model were used to evaluate neutropenic response to single-agent pemetrexed administration. Results: The timecourse of neutropenia following single-agent pemetrexed administration was adequately described by a semimechanistic-physiologic model. Population estimates for system-based model parameters (i.e., baseline neutrophil count, mean transit time, and the feedback parameter), which mathematically represent current understanding of the process and physiology of hematopoiesis, were consistent with previously reported values. The population PK/PD model included homocysteine, cystathionine, albumin, total protein, and BSA as covariates relative to neutropenic response. Conclusion: These results support the programmatic decision to introduce folic acid and vitamin B12 supplementation during pemetrexed clinical development as a means of normalizing patient homocysteine levels, thereby managing the risk of severe neutropenia secondary to pemetrexed administration. The current results also suggest that the addition of vitamin B6 supplementation to normalize patient cystathionine levels may further decrease the incidence of grade 4 neutropenia following pemetrexed administration. The results also suggest the use of folic acid as a means of lessening hematologic toxicity following administration of cytotoxic agents other than antifolates. [ABSTRACT FROM AUTHOR]

Purpose: The objective of these analyses was to examine the effect of variations in the explanatory factors of neutropenic response, identified by semimechanistic-physiologic population pharmacokinetic/pharmacodynamic (PK/PD) modeling, on clinically important features of the absolute neutrophil count (ANC)-time profile (e.g, the nadir of the ANC [NANC], its timing [ T Nadir], and the timecourse of recovery [ T Rec]). Methods: Correlation analyses were used to evaluate the relationship of NANC, T Nadir, and T Rec as a function of overall systemic exposure (AUC) and each of the covariates contained in the population PK/PD model. Simulations using the final PK/PD model were used to generate complete ANC-time profiles. Frequency counts of NANCs from the simulated profiles were used to quantitatively explore differences in the incidence and severity of neutropenia associated with a variety of scenarios (500 mg/m2 versus 600 mg/m2, normal vitamin deficiency markers versus elevated vitamin deficiency markers, and body surface area-based versus renal function-based dosing) and to evaluate the effect of individual explanatory factors with respect to neutropenic response. Results: Information obtained from correlation analysis and simulations was helpful in quantitatively exploring the impact of dose, exposure, and/or patient characteristics on neutropenic response. The information gained from these simulations provided supportive evidence for the decision to routinely include vitamin supplementation during pemetrexed treatment as a means of managing the risk of severe neutropenia secondary to pemetrexed administration. These techniques also provided information regarding the specific T Nadir and T Rec for inclusion in product labeling and suggested that a 14-day treatment cycle might be feasible for pemetrexed. Conclusion: For population PK/PD models, to provide useful information for the practicing clinician or the clinical development team, it is not sufficient to look only at influences of covariates on model parameters. Rather, the modeling results need to be carefully investigated in terms of clinically relevant measures. [ABSTRACT FROM AUTHOR]

Suppose that subjects respond to a battery of questions (items) of a similar nature in a survey, with each item having the same categorical scale. This article discusses models that express logits for the response distributions in terms of subject and item effects. The models, which generalize the Rasch model, have interpretations referring to subject-specific comparisons of the items. Recent literature shows that one can estimate item parameters using estimates of main effect parameters in corresponding quasi-symmetric log-linear models using adjacent-category logits and cumulative logits. For the case of two items, we give expressions for models and corresponding parameter estimates that are the basis of simple tests of marginal homogeneity for square ordinal contingency tables. [ABSTRACT FROM AUTHOR]