Levothyroxine (LT4) is the standard of care for treating hypothyroidism. Despite the established efficacy of LT4, 50% of treated patients fail to achieve normal thyrotropin levels. Oral formulations ...of LT4 that bypass the gastric phase of dissolution may offset some of the therapeutic shortcomings observed with tablets. An oral solution of LT4 can be administered to patients who are unable to swallow tablets; allows flexibility to individualize dosing; and may mitigate interference with LT4 absorption caused by food, coffee, increased gastric pH from atrophic gastritis, and malabsorption from bariatric surgery. The bioavailability of a novel LT4 oral solution and a reference LT4 tablet were compared in a randomized, laboratory-blinded, single-dose, 2-period, 2-sequence, crossover study in healthy euthyroid subjects. A single 600-μg oral dose of LT4 solution (30 mL × 100 μg/5 mL) or tablet (2 × 300-μg tablet) was administered under fasting conditions in each study period, and total thyroxine concentrations were measured for 72 hours after administration. The ratio of geometric least-squares means and 90% confidence intervals for area under the concentration-time curve from time 0 to 72 hours and maximum plasma concentration were calculated. Among 42 subjects in the pharmacokinetic population, the geometric least-squares mean ratio of area under the concentration-time curve from time 0 to 72 hours and maximum plasma concentration for baseline-adjusted thyroxine was 109.1% and 107.9%, respectively, meeting Food and Drug Administration bioequivalence criteria. Adverse events (AEs) were similar between treatment groups with no serious AEs or discontinuations for AEs. Comparable bioavailability was observed between the LT4 oral solution and reference tablet after a single oral 600-μg dose under fasting conditions.
OBJECTIVE:--This study was conducted to determine the effects of vildagliptin on incretin hormone levels, islet function, and postprandial glucose control in subjects with impaired glucose tolerance ...(IGT). RESEARCH DESIGN AND METHODS--A 12-week, double-blind, randomized, parallel-group study comparing vildagliptin (50 mg q.d.) and placebo was conducted in 179 subjects with IGT (2-h glucose 9.1 mmol/l, A1C 5.9%). Plasma levels of intact glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), glucose, insulin, C-peptide, and glucagon were measured during standard meal tests performed at baseline and at week 12. Insulin secretory rate (ISR) was estimated by C-peptide deconvolution. The between-group differences (vildagliptin - placebo) in the adjusted mean changes from baseline to end point in the total and incremental (Δ) area under the curve (AUC)₀₋₂ h for these analytes were assessed by ANCOVA; glucose AUC₀₋₂ h was the primary outcome variable. RESULTS:--Relative to placebo, vildagliptin increased GLP-1 (ΔAUC, +6.0 ± 1.2 pmol · l⁻¹ · h⁻¹, P < 0.001) and GIP (ΔAUC, +46.8 ± 5.4 pmol · l⁻¹ · h⁻¹, P < 0.001) and decreased glucagon (ΔAUC, -3.0 ± 1.0 pmol · l⁻¹ · h⁻¹, P = 0.003). Although postprandial insulin levels were unaffected (ΔAUC, +20.8 ± 35.7 pmol · l⁻¹ · h⁻¹, P = 0.561), prandial glucose excursions were reduced (ΔAUC, -1.0 ± 0.3 mmol · l⁻¹ · h⁻¹, P < 0.001), representing an ~30% decrease relative to placebo. β-Cell function as assessed by the ISR AUC₀₋₂ h/glucose AUC₀₋₂ h was significantly increased (+6.4 ± 2.0 pmol · min⁻¹ · m⁻² · mmol · l⁻¹, P = 0.002). Adverse event profiles were similar in the two treatment groups, and no hypoglycemia was reported. CONCLUSIONS:--The known effects of vildagliptin on incretin levels and islet function in type 2 diabetes were reproduced in subjects with IGT, with a 32% reduction in postprandial glucose excursions and no evidence of hypoglycemia or weight gain.
To evaluate ITCA 650, a continuous subcutaneous miniature osmotic pump delivery system of exenatide versus twice-daily exenatide injections (Ex-BID) in subjects with type 2 diabetes.
We conducted a ...randomized, two-stage, 24-week, open-label, phase 2 study in type 2 diabetes inadequately controlled with metformin. Stage I: 155 subjects were randomized to 20 or 40 μg/day of ITCA 650 or Ex-BID 5 → 10 μg. Stage II: 131 subjects were rerandomized to 20, 40, 60, or 80 μg/day of ITCA 650. Change from baseline for HbA1c, weight, and fasting plasma glucose were evaluated at weeks 12 and 24.
HbA1c was significantly lower in all groups after 12 and 24 weeks. Stage I: mean change in HbA1c from a mean baseline of 7.9-8.0% was -0.98, -0.95, and -0.72% for the 20 and 40 μg/day ITCA 650 and Ex-BID groups, respectively, with 63, 65, and 50% of subjects achieving HbA1c levels ≤ 7% (P < 0.05). Stage II: significant (P < 0.05) reductions in HbA1c (≈ 1.4% from baseline) were achieved with 60 and 80 μg/day ITCA 650, and 86 and 78% of subjects achieved HbA1c ≤ 7% at 24 weeks; respectively. Weight was reduced by 2.8-3.7 kg (P < 0.05) at 24 weeks in all except the 20 → 20 μg/day group. ITCA 650 was well tolerated; nausea was lower and transient with 20 μg/day relative to Ex-BID; and 60 μg/day had the best profile of tolerability and HbA1c lowering.
ITCA 650 significantly reduced HbA1c and weight and was well tolerated. The 20 → 60 μg/day regimen was considered the best dose for further examination in phase 3.
Abstract Background Exenatide, a glucagon-like peptide-1 receptor agonist administered by self-injection, decreases plasma glucose, glycosylated hemoglobin (HbA1c ), and weight in patients with type ...2 diabetes. ITCA 650 is an investigational new drug that provides continuous subcutaneous delivery of exenatide. Objective This randomized, open-label, multicenter, 28-day study evaluated the tolerability, pharmacodynamics, and pharmacokinetics of ITCA 650 in patients with type 2 diabetes. Methods The study enrolled patients with type 2 diabetes who were receiving a stable regimen of diet and exercise alone or a stable dose of metformin monotherapy, thiazolidinedione monotherapy, or metformin plus thiazolidinedione combination therapy. Patients were randomized to receive 10, 20, 40, or 80 μg/d of ITCA 650 placed subcutaneously for 28 days. Plasma glucose, HbA1c , insulin, and weight were measured at regular intervals throughout the study. Exenatide levels and anti-exenatide antibodies were also assessed. Results Forty-four patients were randomized to treatment. From baseline to end point, significant ( P < 0.05) decreases in fasting plasma glucose levels, 2-hour postprandial glucose levels, and glucose AUC curve were seen in all treatment groups. HbA1c levels also decreased significantly ( P < 0.001) in all 4 treatment groups. Weight was significantly ( P < 0.05) lowered in the 40- and 80-μg/d groups. Detectable levels of exenatide were noted within 12 to 24 hours of ITCA 650 placement, reached steady state by 24 hours, and then remained relatively steady during a plateau period until device removal on day 29. Exenatide levels declined to undetectable levels within 24 hours after removal of the ITCA 650. The most common adverse events were nausea, decreased appetite, and vomiting; these were transient and mostly mild or moderate in severity. Mild local adverse events related to the healing process were common at the placement site but abated after 1 week. Twelve patients developed anti-exenatide antibodies; however, the pharmacokinetics of ITCA 650 were not altered compared with those who did not develop antibodies. Conclusions ITCA 650 provided continuous and controlled subcutaneous delivery of exenatide for 28 days that was generally well tolerated and produced significant reductions in plasma glucose, HbA1c , and weight. Further studies are warranted to characterize the long-term tolerability and efficacy of ITCA 650 for the treatment of patients with type 2 diabetes. ClinicalTrials.gov identifier: NCT01798264.
To compare long-term efficacy and safety of initial combination therapy with nateglinide/metformin versus glyburide/metformin.
We conducted a randomized, multicenter, double-masked, 2-year study of ...428 drug-naïve patients with type 2 diabetes. Patients received 120 mg a.c. nateglinide or 1.25 mg q.d. glyburide plus 500 mg q.d. open-label metformin for the initial 4 weeks. During a subsequent 12-week titration period, glyburide and metformin were increased by 1.25- and 500-mg increments to maximum daily doses of 10 and 2,000 mg, respectively, if biweekly fasting plasma glucose (FPG) > or = 6.7 mmol/l. Nateglinide was not titrated. Blinding was maintained by use of matching placebo for nateglinide and glyburide. An 88-week monitoring period followed, during which HbA1c (A1C), FPG, and postprandial glucose excursions (PPGEs) during an oral glucose tolerance test were measured.
In nateglinide/metformin-treated patients, mean A1C was 8.4% at baseline and 6.9% at week 104. In glyburide/metformin-treated patients, mean A1C was 8.3% at baseline and 6.8% at week 104 (P < 0.0001 vs. baseline for both treatments, NS between treatments). The deltaPPGE averaged -96 +/- 19 (P < 0.0001) and -57 +/- 22 mmol.l(-1).min(-1) (P < 0.05) in patients receiving nateglinide/metformin and glyburide/metformin, respectively, whereas deltaFPG was -1.6 +/- 0.2 (P < 0.0001) and -2.4 +/- 0.2 mmol/l (P < 0.0001) in patients receiving nateglinide/metformin and glyburide/metformin, respectively (P < 0.01 between groups). Thus, the two treatments achieved similar efficacy with differential effects on FPG versus PPGE. Hypoglycemia occurred in 8.2 and 17.7% of patients receiving nateglinide/metformin and glyburide/metformin, respectively.
Similar good glycemic control can be maintained for 2 years with either treatment regimen, but nateglinide/metformin may represent a safer approach to initial combination therapy.
The nucleopore is an essential structure of the eukaryotic cell, regulating passage between the nucleus and cytoplasm. While individual functions of core nucleopore proteins have been identified, the ...role of other components, such as Nup210, are poorly defined. Here, through the use of an unbiased ENU mutagenesis screen for mutations effecting the peripheral T cell compartment, we identified a Nup210 mutation in a mouse strain with altered CD4/CD8 T cell ratios. Through the generation of Nup210 knockout mice we identified Nup210 as having a T cell-intrinsic function in the peripheral homeostasis of T cells. Remarkably, despite the deep evolutionary conservation of this key nucleopore complex member, no other major phenotypes developed, with viable and healthy knockout mice. These results identify Nup210 as an important nucleopore complex component for peripheral T cells, and raise further questions of why this nucleopore component shows deep evolutionary conservation despite seemingly redundant functions in most cell types.
Superior Visual Search in Autism O'Riordan, Michelle A; Plaisted, Kate C; Driver, Jon ...
Journal of experimental psychology. Human perception and performance,
06/2001, Letnik:
27, Številka:
3
Journal Article
Recenzirano
Children with a diagnosis of autism and normally developing children, matched for age and general ability, were tested on a series of visual search tasks in 2 separate experiments. The children with ...autism performed better than the normally developing children on difficult visual search tasks. This result occurred regardless of whether the target was uniquely defined by a single feature or a conjunction of features, as long as ceiling effects did not mask the difference. Superior visual search performance in autism can be seen as analogous to other reports of enhanced unique item detection in autism. Unique item detection in autism is discussed in the light of mechanisms proposed to be involved in normal visual search performance.
Background. Cytomegalovirus (CMV) is a major cause of morbidity in transplant recipients. An immunologic predictor of protection against CMV reactivation or disease is highly desirable. Methods. ...Thirty-eight allogeneic hematopoietic stem cell transplant recipients at risk of CMV disease were prospectively monitored using whole blood CMV-DNA polymerase chain reaction assay, lymphocyte proliferation assay (LPA), interferon γ enzyme-linked immunospot assay (ELISPOT), and flow cytometric enumeration of CMV-specific CD69+interferon (IFN)γ+CD4, CD8, natural killer cells, and γδ T cells. Results. Twenty-one subjects developed ⩾1 episode of CMV viremia and 4 developed disease during 360 days of follow-up. Among CMV-seropositive recipients, positive CMV-LPA before transplantation correlated with higher risk of developing viremia after transplantation (P=.02). In contrast, after transplantation, reconstitution of CMV-LPA was significantly associated with absence of CMV viremia over 360 days of follow-up (P=.04) and with faster clearance of viremia during individual episodes of CMV reactivation (P=.03). Reconstitution of CMV-specific natural killer cells was also associated with absence of CMV viremia over 360 days of study (P=.04) but not with faster clearance of viremia. CMV-specific CD4, CD8, γδ T cells, and ELISPOT values were not significantly different in viremic subjects, compared with the corresponding values in nonviremic subjects, at any time point. Conclusions. To our knowledge, this is the first study to prospectively compare multiple measures of innate and adaptive immune responses in hematopoietic stem cell transplant recipients with CMV viremia. The strongest immune correlates with protection against CMV viremia in hematopoietic stem cell transplant recipients are reconstitution of CMV-specific T cell memory responses (LPA) and recovery of natural killer cell function. In contrast, positive CMV-LPA before transplantation may be a marker of high risk of CMV reactivation after transplantation.
Role of endoscopy in the bariatric surgery patient Anderson, Michelle A., MD, MSc; Gan, S. Ian, MD; Fanelli, Robert D., MD ...
Gastrointestinal endoscopy,
07/2008, Letnik:
68, Številka:
1
Journal Article
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