Tapering Canakinumab Monotherapy in Patients With Systemic Juvenile Idiopathic Arthritis in Clinical Remission: Results From a Phase IIIb/IV Open-Label, Randomized Study.

Objective: To evaluate the efficacy and safety of 2 canakinumab monotherapy tapering regimens in order to maintain complete clinical remission in children with systemic juvenile idiopathic arthritis (JIA).

Methods: The study was designed as a 2-part phase IIIb/IV open-label, randomized trial. In the first part, patients received 4 mg/kg of canakinumab subcutaneously every 4 weeks and discontinued glucocorticoids and/or methotrexate as appropriate.

Iron uptake and ferrokinetics in healthy male subjects of an iron-based oral phosphate binder (SBR759) labeled with the stable isotope (58)Fe.

SBR759 is a novel polynuclear iron(III) oxide-hydroxide starch·sucrose·carbonate complex being developed for oral use in chronic kidney disease (CKD) patients with hyperphosphatemia on hemodialysis. SBR759 binds inorganic phosphate released by food uptake and digestion in the gastro-intestinal tract increasing the fecal excretion of phosphate with concomitant reduction of serum phosphate concentrations. Considering the high content of ∼20% w/w covalently bound iron in SBR759 and expected chronic administration to patients, absorption of small amounts of iron released from the drug substance could result in potential iron overload and toxicity.

An iron stable isotope comparison between human erythrocytes and plasma.

We present precise iron stable isotope ratios measured by multicollector-ICP mass spectrometry (MC-ICP-MS) of human red blood cells (erythrocytes) and blood plasma from 12 healthy male adults taken during a clinical study. The accurate determination of stable isotope ratios in plasma first required substantial method development work, as minor iron amounts in plasma had to be separated from a large organic matrix prior to mass-spectrometric analysis to avoid spectroscopic interferences and shifts in the mass spectrometer's mass-bias. The (56)Fe/(54)Fe ratio in erythrocytes, expressed as permil difference from the "IRMM-014" iron reference standard (δ(56/54)Fe), ranges from -3.

Chronopharmacokinetics of mycophenolic acid and its glucuronide and acyl glucuronide metabolites in kidney transplant recipients converted from cyclosporine to everolimus.

Background: The influence of the conversion from cyclosporine (CsA) to everolimus (EVR) on the chronopharmacokinetics of mycophenolic acid (MPA) and its glucuronide (MPAG) and acyl glucuronide (acyl-MPAG) metabolites in patients receiving enteric-coated mycophenolate sodium (EC-MPS) has not been studied.

Methods: We evaluated daytime and nighttime steady-state MPA, MPAG, and acyl-MPAG pharmacokinetics in 24 stable kidney transplant recipients while receiving cyclosporine and 28 days after conversion from CsA to EVR. The effect of concomitant treatment and the circadian difference on AUC(t,ss) and C(max,ss) were assessed using a linear mixed model.

Sotrastaurin single-dose pharmacokinetics in de novo liver transplant recipients.

Sotrastaurin is a protein kinase C inhibitor in development for prevention of rejection after liver transplantation. In a pharmacokinetic study, 13 de novo liver transplant recipients received 100 mg sotrastaurin once between days 1-3 and once between days 5-8 post-transplant. Sotrastaurin absorption based on the area under the concentration-time curve (AUC) of total drug in blood (3544 ± 1434 ng·h/ml) was similar to that of healthy subjects in a previous study (4531 ± 1650 ng·h/ml).

Overview of sotrastaurin clinical pharmacokinetics.

Sotrastaurin (AEB071) is an investigational immunosuppressant that blocks T-lymphocyte activation through protein kinase C inhibition. It is currently in Phase II of clinical development for the prevention of acute rejection after solid organ transplantation. In renal transplant clinical trials, sotrastaurin has been administered at doses of 200 to 300 mg twice daily.

Sotrastaurin and cyclosporine drug interaction study in healthy subjects.

Introduction: Sotrastaurin is an immunosuppressant that inhibits protein kinase C and blocks T-lymphocyte activation. The authors determined the effect of combining sotrastaurin with the calcineurin inhibitor cyclosporine on the pharmacokinetics and biomarker responses to both drugs.

Methods: This was a randomized, 4-period, crossover study in 20 healthy subjects who received single oral doses of (1) sotrastaurin 100 mg, (2) cyclosporine 400 mg, (3) 100 mg sotrastaurin with 100 mg cyclosporine and (4) 100 mg sotrastaurin with 400 mg cyclosporine.

Sotrastaurin and tacrolimus coadministration: effects on pharmacokinetics and biomarker responses.

Sotrastaurin is an immunosuppressant that inhibits protein kinase C. In the prevention of acute rejection in organ transplantation, sotrastaurin might be combined with tacrolimus. A drug interaction study was performed in 18 healthy subjects who received single oral doses of sotrastaurin 400 mg, tacrolimus 7 mg, and the drug combination.

Efficacy and safety of SBR759, a new iron-based phosphate binder.

Treatment of elevated serum phosphorus in hemodialysis patients remains challenging due in part to the lack of a well-tolerated, safe, and effective phosphate binder. Here we report the results of a single-center, open-label, phase I clinical trial of 44 hemodialysis patients to show the safety and efficacy of a novel iron-based phosphate binder, SBR759. After establishing its safety at an initial dose of 3.

Randomized crossover study to assess the inter- and intrasubject variability of morning mycophenolic acid concentrations from enteric-coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients.

The delayed release of mycophenolic acid (MPA) from enteric-coated mycophenolate sodium (EC-MPS, myfortic®) may have an impact on the variability of MPA trough (C0 h) levels. A randomized, two-period crossover study was performed in 24 maintenance renal transplants to evaluate the inter- and intrasubject variability of MPA predose levels from EC-MPS and mycophenolate mofetil (MMF, CellCept®), both in combination with cyclosporine. Patients received EC-MPS (720 mg b.

The effect on sotrastaurin pharmacokinetics of strong CYP3A inhibition by ketoconazole.

Aims: Sotrastaurin is an immunosuppressant that reduces T-lymphocyte activation via protein kinase C inhibition. The effect of CYP3A4 inhibition by ketoconazole on the pharmacokinetics of sotrastaurin, a CYP3A4 substrate, was investigated.

Methods: This was a two-period, single-sequence crossover study in 18 healthy subjects.

The ability of atropine to prevent and reverse the negative chronotropic effect of fingolimod in healthy subjects.

Aims: The authors determined whether intravenous atropine can prevent or counteract the negative chronotropic effect of the immunomodulator fingolimod.

Methods: In this randomized, placebo-controlled, two-period, crossover study, 12 healthy subjects received 5 mg fingolimod orally concurrently with intravenous atropine (titrated to a heart rate of 110-120 beats min(-1)) or intravenous placebo. A second group of 12 subjects received atropine/placebo 4 h after the fingolimod dose.

Development of a shape memory alloy actuator for transanal endoscopic microsurgery.

This paper describes problems in traditional transanal endoscopic microsurgery (TEM), and proposes a mechatronics approach in new design. As one of several actuation mechanisms to expose rectal cavity, a compression coil spring made of shape memory alloy (SMA) has been studied. A custom SMA spring actuator was designed to displace 12 mm with 45 N driving force.

Overview of FTY720 clinical pharmacokinetics and pharmacology.

Drug discovery programs are actively exploring for therapeutic agents targeting enzymes and receptors regulating sphingolipid metabolism and biologic functions. FTY720 is a close structural analogue of sphingosine with immunomodulatory properties. After oral administration, FTY720 is phosphorylated by sphingosine kinase to form the active moiety FTY720-phosphate, which subsequently binds to the sphingosine-1-phosphate receptor.