Efficacy and safety of initial combination treatment with sitagliptin and pioglitazone--a factorial study.

AIM: To evaluate the efficacy and safety of initial combination therapy of sitagliptin 100 mg/day coadministered with all marketed doses of pioglitazone in patients with type 2 diabetes. METHODS: Patients with A1c ≥7.5 and ≤11.0% were randomized among seven arms that received, once daily, 100 mg sitagliptin alone; 15, 30 or 45 mg pioglitazone alone, or 100 mg sitagliptin plus 15, 30 or 45 mg pioglitazone for 54 weeks. The primary endpoint was change from baseline in A1c at week 24. Protocol-specified analyses compared combination therapies with monotherapies at respective dose-strengths and combination of sitagliptin plus pioglitazone 30 mg with pioglitazone 45 mg monotherapy. Post-hoc analyses compared sitagliptin plus pioglitazone 15 mg with pioglitazone monotherapy at the two higher doses. RESULTS: Initial combination therapy with sitagliptin and pioglitazone provided significantly greater reductions in A1c (0.4-0.7% differences) and other glycaemic endpoints than either monotherapy at the same doses. Combining sitagliptin with low-dose pioglitazone generally produced greater glycaemic improvements than higher doses of pioglitazone monotherapy (0.3-0.4% differences in A1c). Combination therapy was generally well tolerated; adverse events (AEs) of hypoglycaemia were reported with similar incidence (7.8-11.1%) in all treatment groups over the 54 weeks of study; oedema was reported in 0.5% of patients in the sitagliptin monotherapy group and 2.7-5.3% among pioglitazone-treated groups. Significant weight gain was observed in all combination-treated groups compared with the sitagliptin monotherapy group. CONCLUSIONS: Initial combination therapy with sitagliptin and pioglitazone provided better glycaemic control than either monotherapy and was generally well tolerated.

The effect of desmopressin on bleeding time and platelet aggregation in healthy volunteers administered ticagrelor.

WHAT IS KNOWN AND OBJECTIVE: Ticagrelor is a reversibly binding and selective P2Y12 -receptor antagonist approved for the prevention of atherothrombotic events in patients with acute coronary syndromes. As bleeding events remain a hazard with antiplatelet therapy, this study investigated the effect of the vasopressin agonist, desmopressin, on ticagrelor-induced bleeding time prolongation. Desmopressin has previously been shown to improve primary haemostasis and is widely used as first-line therapy for individuals with bleeding disorders. METHODS: In a randomized, double-blind, 2-period crossover study, healthy volunteers received ticagrelor (270 mg loading dose; 180 mg bid) for 5 days. On Day 5, desmopressin (0·3 µg/kg) or saline intravenous infusions were administered. The impact of desmopressin on bleeding time, inhibition of platelet aggregation (IPA), platelet function and ticagrelor pharmacokinetic parameters was investigated. RESULTS: Twenty-one volunteers (81% male) were enrolled. Median [range] bleeding times were slightly reduced with ticagrelor plus desmopressin compared with ticagrelor alone (7·50 [3-17] vs. 10·50 [3-25] min at 2·5 h). Median reductions in bleeding time from baseline were generally similar between ticagrelor plus desmopressin compared with ticagrelor alone at all time points. Co-administration of desmopressin had no impact on IPA, although platelet reactivity was significantly increased (von Willebrand Factor antigen: GLS mean AUEC was 4667%.h for ticagrelor plus desmopressin compared with 2750%.h for ticagrelor alone). Desmopressin did not influence the pharmacokinetics of ticagrelor. WHAT IS NEW AND CONCLUSION: Desmopressin had no significant effect on bleeding time or inhibition of platelet aggregation by ticagrelor, although primary haemostatic activity was significantly increased. Ticagrelor pharmacokinetic parameters were not affected by co-administration with desmopressin. Therefore, desmopressin is unlikely to be an effective therapeutic agent for control of the potential bleeding events associated with ticagrelor.

Effect of initial combination therapy with sitagliptin and metformin on ß-cell function in patients with type 2 diabetes.

AIM: To examine the effect of sitagliptin and metformin, alone and in combination, on modelled parameters of ß-cell function in patients with type 2 diabetes. METHODS: The data used in the present analyses are from a 104-week study, which included a 24-week, placebo- and active controlled phase followed by a 30-week, active controlled, continuation phase and an additional 50-week, active controlled extension phase. Patients were randomised to one of six blinded treatments: sitagliptin 50 mg + metformin 1000 mg b.i.d., sitagliptin 50 mg + metformin 500 mg b.i.d., metformin 1000 mg b.i.d., metformin 500 mg b.i.d., sitagliptin 100 mg q.d. or placebo. Patients on placebo were switched in a blinded manner to metformin 1000 mg b.i.d. at week 24. Subsets of patients volunteered to undergo frequently sampled meal tolerance tests at baseline and at weeks 24, 54 and 104. ß-cell responsivity was assessed with the C-peptide minimal model. The static component (Φ(s)) estimates the rate of insulin secretion related to above-basal glucose concentration. The dynamic component (Φ(d)) is related to the rate of change in glucose. The total index (Φ(total)) represents the overall response to a glycaemic stimulus and is calculated as a function of Φ(s) and Φ(d). Insulin sensitivity was estimated with the Matsuda index (ISI). The disposition index, which assesses insulin secretion relative to the prevailing insulin sensitivity, was calculated based on the Φ(total) and ISI. RESULTS: At week 24, substantial reductions in postmeal glucose were observed with all active treatment groups relative to the placebo group. Φ(s), Φ(total) and the disposition index were significantly improved from baseline at week 24 with all active treatments relative to placebo. Generally larger effects were observed with the initial combination of sitagliptin and metformin relative to the monotherapy groups. When expressed as median percent change from baseline, Φ(s) increased from baseline by 137 and 177% in the low- and high-dose combination groups and by 85, 54, 73 and -9% in the high-dose metformin, low-dose metformin, sitagliptin monotherapy and placebo groups, respectively. At weeks 54 and 104, the combination treatment groups continued to demonstrate greater improvements in ß-cell function relative to their respective monotherapy groups. CONCLUSIONS: After 24 weeks of therapy, relative to placebo, initial treatment with sitagliptin or metformin monotherapy improved ß-cell function; moreover, initial combination therapy demonstrated larger improvements than the individual monotherapies. Improvements in ß-cell function were found with treatments for up to 2 years.

Efficacy and safety of initial combination therapy with sitagliptin and pioglitazone in patients with type 2 diabetes: a 54-week study.

AIM: To assess the 54-week efficacy of initial combination therapy with sitagliptin and pioglitazone, compared with pioglitazone monotherapy, and to assess safety in these groups during the 30 weeks after the dosage of pioglitazone was increased from 30 to 45 mg/day, in drug-naÏve patients with type 2 diabetes mellitus and inadequate glycaemic control [haemoglobin A1c (HbA1c) 8-12%]. METHODS: Following a 24-week, randomized, double-blind, parallel-group study (Sitagliptin Protocol 064, Clinicaltrials.gov: NCT00397631; Yoon KH, Shockey GR, Teng R et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and pioglitazone on glycaemic control and measures of beta-cell function in patients with type 2 diabetes. Int J Clin Pract 2011; 65: 154-164) in which patients were treated with the combination of sitagliptin 100 mg/day and pioglitazone 30 mg/day or monotherapy with pioglitazone 30 mg/day, patients entered a 30-week extension study. In the extension study, the pioglitazone dose was increased from 30 to 45 mg/day in both groups. Depending upon treatment allocation, patients took one tablet of sitagliptin 100 mg or matching placebo daily. Pioglitazone was administered in an open-label fashion as a single 45-mg tablet taken once daily. Patients not meeting specific glycaemic goals in the extension study were rescued with metformin therapy. Efficacy and safety results for the extension study excluded data after initiation of rescue therapy. RESULTS: Of the 520 patients initially randomized, 446 completed the base study and, of these, 317 entered the extension. In this extension study cohort, the mean reductions from baseline in HbA1c and fasting plasma glucose (FPG) at the end of the base study (week 24) were -2.5% and -62.1 mg/dl with the combination of sitagliptin 100 mg and pioglitazone 30 mg versus -1.9% and -48.7 mg/dl with pioglitazone monotherapy. At the end of the extension study (week 54), the mean reduction in haemoglobin A1c (HbA1c) was -2.4% with the combination of sitagliptin 100 mg and pioglitazone 45 mg versus -1.9% with pioglitazone monotherapy [between-group difference (95% CI) = -0.5% (-0.8, -0.3)] and the mean reduction in FPG was -61.3 mg/dl versus -52.8 mg/dl, respectively [between-group difference (95% CI) = -8.5 mg/dl (-16.3, -0.7)]. Safety and tolerability of initial treatment with the combination of sitagliptin and pioglitazone and pioglitazone monotherapy were similar. As expected, increases in body weight from baseline were observed in both treatment groups at week 54: 4.8 and 4.1 kg in the combination and monotherapy groups, respectively [between-group difference (95% CI) = 0.7 kg (-0.7, 2.1)]. CONCLUSION: In this study, initial combination therapy with sitagliptin 100 mg and pioglitazone 30 mg increased to 45 mg after 24 weeks led to a substantial and durable incremental improvement in glycaemic control compared with initial treatment with pioglitazone monotherapy during a 54-week treatment period. Both initial combination therapy with sitagliptin and pioglitazone and pioglitazone monotherapy were generally well tolerated (Clinicaltrials.gov: NCT01028391).

Lack of clinically significant pharmacological interactions between ticagrelor and enoxaparin or unfractionated heparin in healthy subjects.

WHAT IS KNOWN AND OBJECTIVE: Patients with acute coronary syndromes (ACS) receive several pharmacological therapies concomitantly, including antiplatelet and anticoagulant agents. As unfractionated heparin (UFH) activates platelets in vitro and in vivo, co-administration with an antiplatelet agent may lead to decreased clinical effectiveness of the latter. The aim was therefore to determine any potential drug-drug interactions between the new oral antiplatelet agent ticagrelor, and UFH or enoxaparin. METHODS: In two open-label, three-period, crossover trials, healthy subjects were randomized to receive ticagrelor alone or with enoxaparin (study 1) or UFH (study 2), or enoxaparin or UFH alone. Ticagrelor plasma concentrations, inhibition of platelet aggregation (IPA), anti-factor Xa levels, activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) were measured. RESULTS: Thirty and 28 subjects completed studies 1 and 2, respectively. Study drugs were generally well tolerated, with no significant bleeding or serious adverse events. Co-administration with enoxaparin or UFH had no significant effect on ticagrelor pharmacokinetics. The effect of ticagrelor on IPA was unimpaired by co-administration of enoxaparin, except for a marginal (-2.9%; 908.7%.h, 881.9%.h) reduction in final extent area under the effect curve (AUEC)(2-12) (95% CI: -51.6%.h, -2.0%.h). Co-administering UFH with ticagrelor caused small decreases in IPA(max) (-3.8%; 94.6%, 91.0%) and AUEC(2-12) (-6.8%; 888.6%.h, 828.3%.h) vs. ticagrelor alone (95% CI: final extent IPA(max) -5.7%, -1.6%; AUEC(2-12) -109.8%.h, -10.8%.h). Ticagrelor had no clinically significant effects on enoxaparin as assessed by anti-factor Xa (study 1), or UFH as assessed by aPTT or ACT (study 2). WHAT IS NEW AND CONCLUSIONS: Enoxaparin and UFH had no effect on the pharmacokinetics and no clinically significant effect on the pharmacodynamics of ticagrelor. Ticagrelor had no clinically significant effects on the pharmacodynamics of enoxaparin or UFH.

Lack of significant food effect on the pharmacokinetics of ticagrelor in healthy volunteers.

WHAT IS KNOWN AND OBJECTIVE: Ticagrelor is the first reversibly binding oral P2Y(12) receptor antagonist and has been approved in the European Union and the USA for the reduction of clinical thrombotic events in patients with acute coronary syndromes. This study aimed to assess the effect of food on ticagrelor pharmacokinetics. METHODS: The study was an open-label, randomized, 2-period crossover single-centre trial; 26 healthy volunteers received a single 270 mg (3×90 mg tablets) ticagrelor dose orally following: (i) a 10-h overnight fast; and (ii) after a standard high-fat, high-calorie breakfast. Ticagrelor and AR-C124910XX (a major pharmacologically active metabolite) plasma concentrations were quantified for pharmacokinetic analysis. RESULTS: Ticagrelor median time to maximum concentration (t(max); 2·5 h vs. 1·5 h) was slightly delayed in the fed vs. fasting state. Maximum concentration of ticagrelor (C(max)) was comparable between the two states with 95% confidence intervals (CI) of the geometric least-squares (GLS) mean ratio (0·85-1·03) being within no-effect limits (0·80-1·25). Ticagrelor exposure was slightly higher with food intake; area under the plasma concentration-time curve from zero to infinity (AUC) was 21% higher compared with fasting state (95% CI of GLS mean ratio=1·13-1·30). For AR-C124910XX, AUC (95% CI of GLS mean ratio=0·93-1·07) was unaffected by food consumption. Median t(max) of the metabolite was slightly longer in the fed than fasting state (3·5 h vs. 1·5 h). Mean C(max) for AR-C124910XX was slightly lower (22%) with food intake vs. fasting (95% CI of GLS mean ratio 0·69-0·88). WHAT IS NEW AND CONCLUSION: Food effects on ticagrelor AUC and AR-C124910XX C(max) were small and are considered to be of minimal clinical significance. Thus, ticagrelor can be administered with or without food.

Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and pioglitazone on glycemic control and measures of ß-cell function in patients with type 2 diabetes.

AIM/HYPOTHESIS: To assess the safety and efficacy of initial combination therapy with sitagliptin and pioglitazone compared with pioglitazone monotherapy in drug-naïve patients with type 2 diabetes. METHODS: A total of 520 patients were randomised to initial combination therapy with sitagliptin 100 mg q.d. and pioglitazone 30 mg q.d. or pioglitazone 30 mg q.d. monotherapy for 24 weeks. RESULTS: Initial combination therapy with sitagliptin and pioglitazone led to a mean reduction from baseline in A1C of -2.4% compared with -1.5% for pioglitazone monotherapy (p<0.001). Mean reductions from baseline were greater in patients with a baseline A1C≥10% (-3.0% with combination therapy vs. -2.1% with pioglitazone monotherapy) compared with patients with a baseline A1C<10% (-2.0% with combination therapy vs. -1.1% with pioglitazone monotherapy). Sixty percent of patients in the combination therapy group vs. 28% in the pioglitazone monotherapy group had an A1C of <7% at week 24 (p<0.001). Fasting plasma glucose decreased by -63.0 mg/dl (-3.5 mmol/l) in the combination therapy group compared with -40.2 mg/dl (-2.2 mmol/l) for pioglitazone monotherapy (p<0.001), and 2-h post meal glucose decreased by -113.6 mg/dl (-6.3 mmol/l) with combination therapy compared with -68.9 mg/dl (-3.8 mmol/l) for pioglitazone monotherapy (p<0.001). Measures related to ß-cell function also improved significantly with combination therapy compared with pioglitazone monotherapy. Combination therapy was generally well-tolerated compared with pioglitazone monotherapy, with similar incidences of hypoglycemia (1.1% and 0.8%, respectively), gastrointestinal adverse events (5.7% and 6.9%, respectively), and oedema (2.7% and 3.5%, respectively). CONCLUSION/INTERPRETATION: Initial combination therapy with sitagliptin and pioglitazone substantially improved glycemic control and was generally well-tolerated compared with pioglitazone monotherapy.

Efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy over 2 years in patients with type 2 diabetes.

AIM: To assess the 104-week efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes and inadequate glycaemic control (HbA(1c) 7.5-11%) on diet and exercise. METHODS: This study was a 50-week, double-blind extension of a 54-week, randomized, double-blind, factorial study of the initial combination of sitagliptin and metformin, metformin monotherapy and sitagliptin monotherapy (104 weeks total duration). Patients assigned to active therapy in the 54-week base study remained on those treatments in the extension study: sitagliptin 50 mg b.i.d. + metformin 1000 mg b.i.d. (higher dose combination), sitagliptin 50 mg b.i.d. + metformin 500 mg b.i.d. (lower dose combination), metformin 1000 mg b.i.d. (higher dose), metformin 500 mg b.i.d. (lower dose) and sitagliptin 100 mg q.d. Patients randomized to receive the sequence of placebo/metformin were switched, in a blinded manner, from placebo to metformin monotherapy uptitrated to 1000 mg b.i.d. beginning at week 24 and remained on higher dose metformin through the extension. RESULTS: Amongst patients who entered the extension study without having initiated glycaemic rescue therapy, least-squares mean changes in HbA(1c) from baseline at week 104 were -1.7% (higher dose combination), -1.4% (lower dose combination), -1.3% (higher dose), -1.1% (lower dose) and -1.2% (sitagliptin). The proportions of patients with an HbA(1c) <7% at week 104 were 60% (higher dose combination), 45% (lower dose combination), 45% (higher dose), 28% (lower dose) and 32% (sitagliptin). Fasting and postmeal measures of glycaemic control and beta-cell function improved in all groups, with glycaemic responses generally maintained over the 104-week treatment period. The incidence of hypoglycaemia was low across all groups. The incidences of gastrointestinal adverse experiences were generally lower in the sitagliptin group and similar between the metformin monotherapy and combination groups. CONCLUSIONS: Initial combination therapy with sitagliptin and metformin and monotherapy with either drug alone provided substantial and sustained glycaemic improvements and were well tolerated over 104 weeks in patients with type 2 diabetes.

Single-dose ticagrelor does not prolong the QT interval in healthy subjects.

UNLABELLED: Ticagrelor (AZD6140), the first reversibly binding oral platelet P2Y12 receptor inhibitor, is currently under development for reduction of thrombotic events in patients with acute coronary syndrome (ACS). OBJECTIVE: This study was designed to assess the potential effects of a single oral dose of ticagrelor on QT interval. METHODS: In this randomized, double-blind, double-dummy, placebo- and positive-controlled, three-way crossover study, 36 healthy males received single doses of ticagrelor 900 mg, moxifloxacin (positive control) 400 mg, or placebo in three treatment periods. This ticagrelor dose is substantially higher than the proposed therapeutic dose (90 mg twice daily after a 180 mg loading dose). QT intervals were assessed from 12-lead digital electrocardiogram (ECG) recordings over 24 h. Plasma levels of ticagrelor and its major metabolite AR-C124910XX were measured. Exploratory analyses of exposure-QTc interval relationships were conducted. Safety assessments were made throughout the study. RESULTS: Mean QTcX, QTcF, and QTcB intervals were similar between ticagrelor and placebo. All point estimates for comparisons between ticagrelor and placebo in QTcX over 24 h post dosing were < 5 milliseconds and all upper confidence limits (UCL) from two-sided 95% confidence intervals were < 10 milliseconds (maximum time-matched mean effect 2.27 milliseconds with UCL 6.05 milliseconds at 12 h). With moxifloxacin, all point estimates and UCLs (except at 24 h post dose) were > 5 milliseconds and > 10 milliseconds, respectively, versus placebo; indicating the study had sufficient sensitivity to detect clinically meaningful changes in QT interval. There was no apparent relationship between ticagrelor or AR-C124910XX levels and QT intervals. Ticagrelor was well tolerated at the tested dose. CONCLUSIONS: A single oral dose of 900 mg ticagrelor did not prolong the QT interval in healthy volunteers compared with placebo. Thus, it is expected that ticagrelor will not affect cardiac repolarization in ACS patients.

High-glucose promotes proliferation of human bladder cancer T24 cells by activating Wnt/ß-catenin signaling pathway.

OBJECTIVE: Bladder cancer is the most prevalent genitourinary malignant disorder worldwide. We aimed to observe effects of high-glucose on bladder cancer proliferation and explore the associated mechanisms. MATERIALS AND METHODS: Human bladder cancer cell line, T24, was divided into Blank, Control (Ctrl), 10 mmol/l, 20 mmol/l and 30 mmol/l group. T24 cell proliferation was evaluated by using multiple table tournament (MTT) assay and colony formation analysis, respectively. Quantitative Real-time PCR (qRT-PCR) assay was employed to examine mRNA expression of Wnt-5a and ß-catenin. Meanwhile, Western blot assay was used to evaluate expression of Wnt-5a and ß-catenin protein. The linear regression analysis was utilized to analyze correlation between Wnt-5a/ß-catenin expression and T24 cell proliferation. RESULTS: High-glucose significantly enhanced proliferation of T24 cells compared to that of Blank and Ctrl group (p < 0.05). High-glucose significantly promoted colony formation of T24 cells compared to that of Blank and Ctrl group (p < 0.05). High-glucose significantly up-regulated Wnt-5a mRNA and protein expression compared to that of Blank and Ctrl group (p < 0.01). High-glucose significantly increased ß-catenin mRNA and protein expression compared to that of Blank and Ctrl group (p < 0.01). Effects of high-glucose on T24 cell proliferation were increased following with the enhanced glucose concentration. Wnt/ß-catenin signaling pathway molecules were correlated with colony formation of T24 cells (p < 0.05). CONCLUSIONS: High-glucose promoted the proliferation of T24 cells by activating the Wnt/ß-catenin signaling pathway. This study would provide the novel targets for bladder cancer therapy.

Identification and characterization of a new type of asymmetrical dicentric chromosome derived from a single maternal chromosome 18.

Molecular cytogenetic analysis identified a new type of dicentric chromosome involving different breakpoints at 18q in a female fetus. The chromosome anomaly was designated as an asymmetrical pseudoisodicentric chromosome 18, 46,XX,psu dic(18)(pter-->q11.2::q21.3-->pter)mat. A series of BAC clones for 18q11.2 and q21.3 regions were used to identify one breakpoint within the region q11.2 between 19.8 and 21.6 Mb from the telomere of 18p and another breakpoint within q21.3 between 55.4 and 56.9 Mb from the telomere of 18p by FISH analysis. Real-time quantitative PCR and microsatellite analysis further verified that the dicentric chromosome was maternal in origin and resulted from a break-reunion between sister chromatids of a single maternal chromosome. We propose that a loop-type configuration of sister chromatids took place and that the break-reunion occurred at cross sites of the loop to form an asymmetrical isodicentric chromosome during either mitosis or meiosis. In this case, the asymmetrical pseudoisodicentric resulted in an 18pter--> q11.2 duplication and an 18q21.3-->qter deletion, which could have led to certain dysmorphic features of 18q- syndrome in this fetus.

Early neonatal hypotension in premature infants born to preeclamptic mothers.

BACKGROUND: Early neonatal hypotension (ENH) is common in premature infants and has been claimed to occur more frequently in infants born to mothers with severe preeclampsia. Previous studies that showed a relationship between maternal preeclampsia and neonatal hypotension did not control for potential confounding factors such as birth weight and maternal treatment with magnesium sulfate (MgSO4). OBJECTIVE: To determine whether maternal preeclampsia is an independent risk factor for ENH. STUDY DESIGN: We conducted a retrospective review of all viable singleton infants with gestational age of 23 to 30 weeks who were admitted to the neonatal intensive care unit over a 2-year period. ENH was defined as the persistence of the mean arterial pressure lower than the gestational age in weeks requiring volume expansion and inotropic support in the first 24 h of life. RESULTS: One hundred and eighty four infants were enrolled. Seventy-five (41%) infants met the diagnostic criteria for ENH. Maternal preeclampsia, the presence of labor, maternal treatment with MgSO4, Apgar scores, birth weight, gestational age and respiratory distress syndrome were significantly associated with ENH by univariate analysis. Only gestational age and maternal preeclampsia were significantly associated with ENH by multiple logistic regression. CONCLUSION: Gestational age and maternal preeclampsia were independent risk factors for ENH in our population of premature infants.

Effects of autologous platelet transfusion on platelet inhibition in ticagrelor-treated and clopidogrel-treated subjects.

Essentials Limited data on hemostatic benefits of platelet transfusion (PT) exist. 44 healthy subjects had a single dose of ticagrelor or clopidogrel ± autologous PT post-dosing. PT did not reverse ticagrelor's antiplatelet effects and had minimal impact post clopidogrel. Post-ticagrelor, PT is unlikely to be beneficial, and the benefits post-clopidogrel are unknown. SUMMARY: Background Antiplatelet agents increase bleeding risk. Few data on hemostatic benefits of platelet transfusion exist. Objective To assess the effect of autologous platelet transfusion on ticagrelor-mediated and clopidogrel-mediated platelet inhibition in a single-center, open-label, randomized, cross-over study (NCT01744288). Methods Forty-four healthy subjects received ticagrelor (180 mg) or clopidogrel (600 mg; two functional CYP2C19 alleles [*1 or *17] required) with or without platelet transfusion (14-day washout). Subjects received one autologous platelet apheresis unit (approximately six pooled donor platelet units) 24 h (n = 15) or 48 h (n = 13) after ticagrelor or 48 h after clopidogrel (n = 16). Platelet apheresis was conducted 72 h before transfusion. Aspirin (81 mg per day) was taken from after apheresis until 24 h before transfusion. P2Y12 reaction units (PRUs) and inhibition of platelet aggregation (IPA) induced by ADP were measured. Results Mean age and body mass index were 30 years (standard deviation [SD] 6 years) and 26.9 kg m-2 (SD 4.0 kg m-2 ), respectively; 98% of subjects were men, and 39 of 44 completed treatment. Platelet transfusion 24 h after ticagrelor had minimal effects on IPA or PRU values within 48 h after transfusion. Platelet transfusion 48 h after ticagrelor also had minimal effects on IPA or PRU values at most post-transfusion times. Platelet transfusion 48 h after clopidogrel, versus no transfusion, had a small reversing effect on IPA (24 h, 36 h, and 48 h) and PRU values (12 h, 24 h, and 36 h) after transfusion. Conclusions Autologous platelet transfusion is unlikely to be of clinical benefit in reversing the antiplatelet effects of ticagrelor. The clinical relevance of the small effects seen with clopidogrel is unknown.

Numb induces e-cadherin adhesion dissolution, cytoskeleton reorganization, and migration in tubular epithelial cells contributing to renal fibrosis.

Numb, an endocytic protein, is involved in both neural differentiation and protein post-endocytic trafficking. Although negative Numb expression has been linked to human mammary carcinomas, little is known about its expression and functions in other diseases. In the present study, we observed that Numb is expressed in renal tubule epithelia and its expression is increased in the fibrotic kidney in vivo. We determined that in proximal tubular epithelial cells (NRK52E cells), TGF-ß1 induces the expression of Numb and ectopic expression of Numb leads to dissolution of E-cadherin adhesion, reorganization of cytoskeleton, activation of Rac1 and Cdc42, and enhancement of migration. Either knockdown of α-adaptin or overexpression of Numb asparagine-proline-phenylalanine (NPF) mutant interferes with AP-2 dependent endocytosis and rescues Ecadherin level in NRK52E cells. Moreover, knockdown of integrin ß1 or α-adaptin, and overexpression of a Numb dominant-negative form (Numb phosphotyrosine binding [PTB] domain) impair integrin endocytosis, and markedly inhibit Numb-induced cell migration and activation of Rac1 and Cdc42. Taken together, our work identifies Numb as an important player in renal fibrosis, by regulating epithelial-to-mesenchymal transition (EMT) process including E-cadherin adhesion dissolution, actin reorganization, and migration enhancement in NRK52E cells.

Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates.

OBJECTIVE: To evaluate the clinical effects of magnesium sulfate (MgSO4) in the treatment of persistent pulmonary hypertension of the newborn (PPHN) in premature infants. METHODS: This was a prospective, nonrandomized, clinical study. Seven premature neonates with PPHN were treated with MgSO4 as soon as documentation of an interatrial right-to-left shunt was made. A loading dose of 200 mg/kg was infused over 30 minutes, followed by a maintenance dose of 20 to 50 mg/kg/h. Alveolar-arterial oxygen tension difference (AaDO2) and oxygenation index were followed up sequentially as the primary outcome measures. Blood pressures and serum electrolytes were also monitored. RESULTS: Six cases responded clinically. The decrease of AaDO2 reached significance at 36 hours, but the decrease of oxygenation index was not significant over 72 hours. Four infants survived. No significant side effects were encountered. CONCLUSION: Our results suggest that MgSO4 may be considered as an alternative treatment of PPHN in premature infants.

No-carrier-added N-(3-[18F]fluoropropyl)spiroperidol: biodistribution in mice and tomographic studies in a baboon.

Two potential radioligands, no-carrier-added (NCA) N-(2-[18F]fluoroethyl)spiroperidol (3) and N-(3-[18F]fluoropropyl)spiroperidol (4) have been synthesized for PET imaging of dopamine receptors in humans. Compounds 3 and 4 were synthesized by N-alkylation of spiroperidol with NCA 1-bromo-2-[18F]-fluoroethane (2b), 1-[18F]fluoro-3-iodopropane (2c) and 1-bromo-3-[18F]fluoropropane (2d) respectively. The biodistribution of 4 in mice showed that the mouse brain uptake of radioactivity was similar to that of [18F]-N-methylspiroperidol (1.1% of the administered dose), but the activity in bone (femur) increased with time. The kinetic distribution of compound 4 in baboon brain was similar to that of [18F]-N-methylspiroperiodol, and the striatal accumulation of radioactivity was also blocked stereoselectively by butaclamol. The ratio of striatum to cerebellum radioactivities at 3 hr after injection was 5.9. Analysis of the metabolic stability of 4 in mouse brains for 1 hr indicated that, like [18F]-N-methylspiroperidol, it is relatively stable to metabolic transformation in the central nervous system. These results suggest that compound 4 may be a useful radioligand for PET studies of the dopamine receptor in humans.

Jacobsen distal 11q deletion syndrome with a myelodysplastic change of hemopoietic cells.

We describe a male infant with unusual facial appearance, relative pancytopenia, bilateral simian creases, and an accessory nipple. Cytogenetic analysis showed deletion of the long arm of chromosome 11 [46,XY,del(11)(pter-->q23.2:)]. Bone-marrow study showed a myelodysplastic change of hemopoietic cells compatible with peripheral blood findings. Pachygyria of the temporal and frontal lobes was demonstrated by magnetic resonance image (MRI) of the brain. We present our findings in order to contribute to the information on 11q23 deletion.

Endoscopic retrograde cholangiopancreatography in infants and children.

A single institutional experience with endoscopic retrograde cholangiopancreatography (ERCP) in pediatric patients was reviewed, focusing on the method of anesthesia, choice of an endoscope, indications, and complications. The medical records of 50 ERCPs performed in 42 infants and children (14 male and 28 female) were reviewed retrospectively. The patients' ages ranged from 57 days to 15 years. Forty-four ERCPs were diagnostic and 6 were therapeutic, including incision of choledochocele, and sphincterotomy and extraction of pancreatic stones. All procedures were successful. The most common indication for ERCP was to evaluate congenital biliary dilatation, in 28 patients (67%). Mild cholangitis occurred as a complication in 1 patient, but was alleviated with medication. A conventional duodenoscope could be used in patients older than 10 years. A pediatric duodenoscope was always used in patients under 1 year of age. Either type was chosen individually for those aged 1 to 10 years depending on the purpose, diagnostic or therapeutic. It is noteworthy that ERCP and/or sphincterotomy in a 1-year-old infant and two 2-year-old children were safely performed with the conventional endoscope. General anesthesia was employed in those younger than 9 years and intravenous sedation and local anesthesia in those older than 11 years. For children aged 9 to 11 years, anesthesia was chosen individually. We concluded that ERCP is a relatively easy and safe technique even for infants and children when performed by skilled hands with an appropriate duodenoscope under suitable anesthesia. The minimum age for use of the conventional duodenoscope may be 1 year.

Nitric oxide and peroxynitrite in the perinatal period.

Many of the actions of nitric oxide are not due to nitric oxide itself, but rather by the secondary formation of oxidants like peroxynitrite. Peroxynitrite leaves a footprint in the nitration of tyrosine, which helps track the formation of reactive nitric oxide-derived species in diseases and even normal development.

Pharmacokinetics and metabolism of single oral doses of trovafloxacin.

Trovafloxacin, a new fluoronaphthyridone derivative related to fluoroquinolone antimicrobial drugs, has demonstrated the following characteristics: significant gram-positive and gram-negative activity; significant activity against anaerobes and atypical respiratory pathogens; approximately 11-hour elimination half-life, permitting once-daily administration; and good tissue penetration. Because <10% of an orally administered dose is recovered in urine as unchanged drug, the predominant route of trovafloxacin elimination appears to be nonrenal. The two studies described in this review examined the metabolism and excretion of trovafloxacin and compared the time course and concentrations of trovafloxacin and its metabolites in bile to those in serum. In the first study, four healthy male volunteers received a single, oral 200-mg dose of radiolabeled trovafloxacin. In the second study, three patients with indwelling nasobiliary tubes received a single 200-mg dose of trovafloxacin. Samples of blood, urine, bile, and feces were collected. Trovafloxacin in urine and serum was analyzed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection and in bile by HPLC-mass spectroscopy (MS). Levels of the N-acetyl metabolite in bile were determined by HPLC/UV/MS. Metabolites in serum, urine, and feces were determined by reverse-phase HPLC/MS, and radioactivity in these samples was assayed by liquid scintillation counting. In the first study, 63.3% and 23.1% of total radioactivity were recovered in feces and urine, respectively, with most of the radioactivity in urine in the form of the ester glucuronide metabolite (12.8%) and unchanged trovafloxacin (5.9%). Unchanged drug, the N-acetyl metabolite, and the N-sulfate of trovafloxacin accounted for 43.2%, 9.2%, and 3.9%, respectively, of the radioactivity in feces. In the second study, biliary trovafloxacin concentrations were highest between 1.5 and 10 hours postdose, and the maximum concentrations ranged from 18.9 to 37.9 microg/mL. The mean bile:serum ratio of trovafloxacin was 14.9, and the biliary concentration of parent drug was higher than that of its N-acetyl metabolite. In both studies, trovafloxacin was well tolerated, with no discontinuations due to adverse events. The pharmacokinetic profile of trovafloxacin in serum was consistent in healthy subjects and in individuals who had undergone recent hepatobiliary surgery. Trovafloxacin is metabolized primarily by the liver, through phase II metabolism (glucuronidation 13.2%, N-acetylation 10.4%, and N-sulfoconjugation 4.1%); minimal oxidative metabolism was detected. Renal elimination accounted for <10% of the administered dose. The high bile to serum ratio and higher trovafloxacin concentrations relative to metabolite concentrations are consistent with nonrenal elimination. These pharmacokinetic and pharmacodynamic results, together with a broad antimicrobial spectrum, long 11-hour elimination half-life, and low drug-interaction potential, suggest that trovafloxacin may be particularly appropriate for use in the surgical setting.