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The incorporation of silicon and oxygen into hydrogenated amorphous carbon (a-C:H) is an effective approach to decrease the dependence of the tribological properties of a-C:H on the environment. Here, we evaluate the effect of hydrogen and oxygen partial pressures in vacuum on the tribological response of steel pins sliding against films consisting of silicon- and oxygen-containing a-C:H (a-C:H:Si:O). Experiments are conducted in the low-friction/low-wear regime, where sufficient gas pressure prevents steel from adhering to the a-C:H:Si:O, with the velocity accommodation mode being interfacial sliding between the tribotrack formed in the a-C:H:Si:O film and the carbonaceous tribofilm that is formed on the countersurface. The experiments indicated a decrease (increase) in friction and wear with the hydrogen (oxygen) pressure (hydrogen pressures between 50 and 2000 mbar; oxygen pressures between 10 and 1000 mbar). Characterization by X-ray photoelectron and absorption spectroscopies indicated the occurrence of tribologically induced rehybridization of carbon-carbon bonds from sp

We conducted atomic force microscopy (AFM) experiments by sliding hard tetrahedral amorphous carbon (ta-C)-coated and diamond AFM probes against silicon oxide-doped hydrogenated amorphous carbon (a-C:H:Si:O) films. We reproducibly observe a substantial reduction in friction with repeated sliding. This behavior qualitatively resembles the run-in effects generally seen in macroscale frictional sliding on diamond-like carbons (DLCs), including this a-C:H:Si:O film in particular. As the applied normal load is increased with repetitive sliding, the friction reduces in tandem. The lateral stiffness of the nanoscale contact is measured as a function of applied normal load, thus the real contact area and the interfacial shear strength are inferred throughout the sliding experiments. These measurements show that the friction reduction is caused by a reduction in the interfacial shear strength of the contact. We propose that this arises from sliding-induced structural modification of the a-C:H:Si:O film. The calculated shear strengths are more than an order of magnitude higher than estimates from macroscale friction experiments. Additionally, humidity-controlled experiments show no significant humidity dependence of the friction despite a very strong dependence at macroscale. Reasons for these contradictions with macroscale experiments are discussed.

BI 655064 is a humanized antagonistic anti‐cluster of differentiation (CD) 40 monoclonal antibody that selectively blocks the CD40‐CD40L interaction. The CD40‐CD40L pathway is a promising treatment target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and lupus nephritis. The safety, tolerability, pharmacokinetics, and pharmacodynamics of repeated once‐weekly BI 655064 subcutaneous dosing over 4 weeks were evaluated in a multiple‐dose study in healthy subjects. Subjects (N = 40) were randomized 4:1 to four sequential BI 655064 dose groups (80, 120, 180, 240 mg) or to placebo. Safety and tolerability, plasma exposure, CD40 receptor occupancy, and CD40L‐induced CD54 upregulation were assessed over 64 and 78 days for the 80‐ to 180‐mg and 240‐mg dose groups, respectively. BI 655064 exposure increased in a supraproportional manner, due to target‐mediated drug clearance, for doses between 80 mg and 120 mg, but was near proportional for doses greater than 120 mg. Terminal half‐life ranged between 6 and 8 days. Dose‐dependent accumulation of BI 655064 supports the use of a loading dose in future clinical studies. Following 4 weeks of dosing, >90% CD40 receptor occupancy and inhibition of CD54 upregulation were observed at all dose levels, lasting for 17 days after the last dose. BI 655064 was generally well tolerated. There were no serious adverse events and the frequency and intensity of adverse events were similar for BI 655064 and placebo; no dose relationship or relevant signs of an acute immune reaction were observed. These findings support further investigation of BI 655064 as a potential treatment for autoimmune diseases.

Low thermal stability is a major limitation of diamond-like carbon (DLC) films, especially amorphous hydrogenated carbon (a-C:H) films, inhibiting their use in several applications. Adding silicon and oxygen to a-C:H increases thermal stability, but mechanisms for this increase are unknown. Reactive molecular dynamics (MD) simulations using the ReaxFF potential were performed on undoped a-C:H and a-C:H containing Si and O (a-C:H:Si:O). As in experiments, the simulated a-C:H:Si:O demonstrated increased thermal stability compared to a-C:H. Atomistic thermal degradation pathways were examined to understand the origins of the enhanced thermal stability of a-C:H:Si:O compared to a-C:H. The primary thermal degradation pathway in undoped a-C:H was the breaking of tensile strained C-C bonds resulting in a transformation of sp3 to sp2-hybridized carbon. The presence of Si suppresses this mechanism by decreasing the frequency of occurrence of highly strained C-C bonds in the unannealed structure. This is due to the longer C-Si equilibrium bond length compared to C-C bonds, which allows the Si-doped films to accommodate higher structural disorder.

Harsh environments pose materials durability challenges across the automotive, aerospace, and manufacturing sectors, and beyond. While amorphous carbon materials have been used as coatings in many environmentally-demanding applications owing to their unique mechanical, electrical, and optical properties, their limited thermal stability and high reactivity in oxidizing environments have impeded their use in many technologies. Silicon- and oxygen-containing hydrogenated amorphous carbon (a-C:H:Si:O) films are promising for several applications because of their higher thermal stability and lower residual stress compared to hydrogenated amorphous carbon (a-C:H). However, an understanding of their superior thermo-oxidative stability compared to a-C:H is lacking, as it has been inhibited by the intrinsic challenge of characterizing an amorphous, multi-component material. Here, we show that introducing silicon and oxygen in a-C:H slightly enhances the thermal stability in vacuum, but tremendously increases the thermo-oxidative stability and the resistance to degradation upon exposure to the harsh conditions of low Earth orbit (LEO). The latter is demonstrated by having mounted samples of a-C:H:Si:O on the exterior of the International Space Station via the Materials International Space Station (MISSE) mission 7b. Exposing lightly-doped a-C:H:Si:O to elevated temperatures under aerobic conditions or to LEO causes carbon volatilization in the near-surface region, producing a silica surface layer that protects the underlying carbon from further removal. These findings provide a novel physically-based understanding of the superior stability of a-C:H:Si:O in harsh environments compared to a-C:H.

Silicon- and oxygen-containing hydrogenated amorphous carbon (a-C:H:Si:O) coatings are amorphous thin-film materials composed of hydrogenated amorphous carbon (a-C:H), doped with silicon and oxygen. Compared to a-C:H, a-C:H:Si:O exhibits much lower susceptibility to oxidative degradation and higher thermal stability, making a-C:H:Si:O attractive for many applications. However, the physical mechanisms for this improved behavior are not understood. Here, the thermally induced structural evolution of a-C:H:Si:O was investigated in situ by X-ray photoelectron and absorption spectroscopy, as well as molecular dynamics (MD) simulations. The spectroscopy results indicate that upon high vacuum annealing, two thermally activated processes with a Gaussian distribution of activation energies with mean value E and standard deviation σ take place in a-C:H:Si:O: (a) ordering and clustering of sp2 carbon (E ± σ = 0.22 ± 0.08 eV) and (b) conversion of sp3- to sp2-bonded carbon (E ± σ = 3.0 ± 1.1 eV). The experimental res...

Purpose The CD40–CD40L pathway is a promising treatment target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and lupus nephritis. The safety, pharmacokinetics and pharmacodynamics of BI 655064, a novel humanised antagonistic anti-CD40 monoclonal antibody, were investigated in this first-in-human trial. Methods Healthy male subjects (n = 72) were randomised 3:1, within each BI 655064 dose group, to single intravenous (IV; 0.2–120 mg) or subcutaneous (SC; 40–120 mg) doses of BI 655064 or placebo. Safety, plasma exposure, CD40 receptor occupancy and CD40L-induced CD54 upregulation were assessed over 12 weeks. Results Adverse events (AEs) were reported in 43% of subjects (n = 31). Frequency and intensity of AEs were generally similar between BI 655064 and placebo and showed no dose relationship. The most frequent AEs were headache and nasopharyngitis. One mild rash and one local reaction occurred with SC BI 655064; two serious AEs were reported, both judged unrelated to BI 655064. Pharmacokinetic evaluation demonstrated a more than proportional increase in plasma exposure relative to BI 655064 dose, with a terminal half-life between 4 h and 4 days IV and approximately 5 days SC; doses ≥ 20 mg IV and 120 mg SC showed > 90% CD40 receptor occupancy and inhibition of CD54 upregulation, which lasted 7 days in the 120 mg IV and SC groups. Conclusions Single doses up to 120 mg BI 655064 IV and SC were well tolerated and showed a high potential to block the CD40–CD40L pathway, supporting further clinical development of BI 655064 in patients with autoimmune disease. Trial registration ClinicalTrials.gov Identifier: NCT01510782 Electronic supplementary material The online version of this article (10.1007/s00228-017-2362-8) contains supplementary material, which is available to authorized users.

BI 1021958, a novel antagonist of the chemoattractant-receptor-homologous molecule (CRTH2), targets airway inflammation in asthma by inhibiting prostaglandin binding to CRTH2 receptors. Two phase 1 studies assessed BI 1021958 safety/tolerability and pharmacokinetics (PK)/pharmacodynamics (PD) following single doses in healthy men and multiple doses in men/women with well-controlled asthma. Studies 1 had 2 parts: a placebo-controlled, fixed-sequence, single-blind, single-rising-dose part (n = 56) and a randomized, 2-way crossover, open-label, repeated-dose part studying the food effect on PK/PD (n = 12). Study 2 was a placebo-controlled, single-center, double-blind multiple-rising-dose study (n = 84). Primary end points were safety/tolerability and PK/PD (both studies); secondary end points were eosinophil shape change (ESC; study 1) and dose proportionality/linearity following first dose and at steady state (study 2). BI 1021958 was adequately tolerated in both studies; adverse events were infrequent, generally mild to moderate, and occurred similarly in treatment groups. Maximum measured concentration (Cmax) was achieved in ≤2.5 hours in study 1 and ≤2.0 hours in study 2. BI 1021958 exposure increased proportionally with dose. In study 1, following a single 60-mg dose, AUC parameters and Cmax were 20% and 15% lower, respectively, after a high-fat meal compared with the fasted state. After ≥60-mg single doses (study 1) and >40-mg multiple doses (study 2), >95% ESC inhibition was observed for ≥24 hours. PK/PD was similar in healthy subjects and subjects with well-controlled asthma. Data support further investigation of CRTH2 antagonists for the treatment of asthma.

A custom-grown silicon and oxygen-containing hydrogenated amorphous carbon (a-C:H:Si:O) film is subjected to ball-on-flat tribometry under controlled sliding environments (ambient, dry air, and dry N2) at room temperature using a 52100 steel ball. The resulting friction coefficient is below 0.2 in ambient air and below 0.1 in dry N2. Tribofilms on the steel ball with thicknesses in excess of 500 nm are observed. The tribofilms are derived from the a-C:H:Si:O and grow on the steel ball, and display chemical and structural modifications relative to the original a-C:H:Si:O film. Sliding of the tribofilm-coated steel ball against bare silicon results in low friction, highlighting the inherent lubricity afforded by the tribofilm. Tribofilms grown through sliding against a-C:H:Si:O are characterized, post-sliding, with multiple spectroscopic and imaging techniques which collectively demonstrate that the composition and structure of the tribofilm is strongly dependent on the sliding environment. The unusually high tribofilm thickness allows for nanoindentation analysis, which demonstrates that the films are laterally heterogenous and softer than the original a-C:H:Si:O, with moduli and hardness values ranging over three orders of magnitude. Many regions of the tribofilms are extremely soft, with measured hardness values below 100 MPa and reduced Young’s moduli below 1 GPa, and also show a viscous mechanical response. Transmission electron microscopy and electron energy loss spectroscopy (TEM/EELS) characterization of the tribofilm demonstrates that the bulk structure is not graphitic, and indicates the tribofilms are enriched in C−H bonding. Additionally, there is a marked segregation within the tribofilm of Si/O and carbon. It is proposed that a primarily polymeric tribofilm structure can explain the observed mechanical properties.

Summary Background The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events. Methods We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50–0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II–IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed. Findings Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase. Interpretation At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis. Funding National Institutes of Health, National Institute of Neurological Disorders and Stroke.

When preparing for clinical trials in myotonic dystrophy type-1 (DM1), it is important that researchers develop and identify patient-reported outcome measures with good measurement properties.Fifty-two DM1 patients enrolled in 2 clinical studies completed the Myotonic Dystrophy Health Index (MDHI), 36-Item Short Form Health Survey (version 2; SF-36v2), Individualized Neuromuscular Quality of Life questionnaire (INQoL), and a questionnaire comparing the relevance, usability, overall preference, and perceived responsiveness of each measure. The associations between instrument scores and physical function, genetic test results, and employment status were examined.The MDHI was preferred over the INQoL in 13 of 13 areas and was preferred over the SF-36v2 in 9 of 13 areas. The MDHI was the only score that was associated with participant employment status, CTG repeat length, and the 3 measurements of clinical function.The MDHI correlates well with physical function and is viewed favorably by participants in DM1 clinical studies. Muscle Nerve, 2018.

SummaryPurpose BI 831266 is a potent, selective, low-molecular-weight inhibitor of Aurora kinase B. This trial aimed to determine the maximum tolerated dose (MTD) of BI 831266 in patients with advanced solid tumors (NCT00756223; EudraCT 2008-001631-36; 1257.1). Methods BI 831266 (4–130 mg) was administered over 24 h on days 1 and 15 of a 4-week schedule. A modified 3 + 3 dose-escalation design was utilized to evaluate the MTD. Safety, pharmacokinetics, pharmacodynamics, objective response rate, progression-free survival (PFS) and exploratory biomarkers were secondary endpoints. Results Twenty-five patients received BI 831266. The most frequent tumor type was colorectal cancer (48 %). One patient (130 mg) experienced a dose-limiting toxicity of grade 3 febrile neutropenia. The trial was prematurely terminated (sponsor decision) without further dose-escalation. The most frequent treatment-related adverse events (AEs) were fatigue (20 %), neutropenia, alopecia (16 % each), anemia, dry skin, and nausea (12 % each). Treatment-related grade ≥3 AEs were neutropenia (12 %), anemia (8 %), and febrile neutropenia (4 %); 15 patients experienced serious AEs. High variability in the pharmacokinetic profiles precluded definitive pharmacokinetic conclusions. Exploratory biomarker determination revealed consistency with the mode of action as an Aurora kinase B inhibitor. One patient (4 %; 32 mg) with cervical cancer demonstrated a confirmed partial response (duration 141 days, PFS 414 days). Four patients had stable disease. Conclusion The MTD of BI 831266 was not reached because of early trial termination. BI 831266 demonstrated a generally manageable safety profile and signs of antitumor activity in some patients’ solid tumors.

Purpose This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and antitumor activity of the Aurora B kinase inhibitor BI 811283 in patients with advanced solid tumors. Methods BI 811283 was administered via 24-h infusion on Days 1 and 15 of a 4-week cycle (schedule A) or Day 1 of a 3-week cycle (schedule B) in a modified 3 + 3 dose-escalation design. Pharmacodynamic assessments included immunohistochemistry for phosphorylated histone H3 (pHH3) on skin biopsies to determine Aurora B kinase inhibition and plasma concentrations of caspase-cleaved CK-18 (apoptosis marker). Results A total of 121 patients were treated. The MTDs of BI 811283 were 125 mg (schedule A) and 230 mg (schedule B). Dose-limiting toxicities were primarily hematological (febrile neutropenia and grade 4 neutropenia); the most common drug-related adverse effects included neutropenia, fatigue, leukopenia, nausea, alopecia, diarrhea, and decreased appetite. A trend toward a decrease in pHH3 was observed, with increasing BI 811283 doses, indicating target engagement; there was no consistent trend regarding caspase-cleaved CK-18 levels. No objective response was observed although 19 patients in each schedule achieved clinical benefit (stable disease). Conclusions BI 811283 demonstrated a generally manageable safety profile and disease stabilization in some patients. Trial registration EudraCT No: 2007-000191-17, ClinicalTrials.gov Identifier: NCT00701324.

Monocyte chemoattractant protein-1 (MCP-1, CCL-2) binds to the Duffy antigen (DARC) on red blood cells, which act as a sink for several chemokines including MCP-1. In this study it is hypothesized that DARC may alter the pharmacokinetics of infused recombinant human MCP-1 (rhMCP-1). The primary aim of this first in man trial is to compare the pharmacokinetics of rhMCP-1 in Duffy positive and negative individuals. A randomized, double-blinded, placebo-controlled dose escalation trial was conducted on 36 healthy volunteers. Subjects received infusions of 0.02–2.0 μg/kg rhMCP-1 or placebo for one hour. RhMCP-1 displayed linear pharmacokinetics. Duffy negative individuals reached maximal plasma levels significantly earlier, but overall plasma concentration profiles were not altered. rhMCP-1 markedly increased monocyte counts, and estimated EC50 values were 10-fold higher in Duffy positive than in Duffy negative subjects. Increased monocyte counts were associated with decreased surface expression of intercellular adhesion molecule 1 (ICAM-1, CD54). In contrast, neither CCR-2 or CD11b expression, nor markers of platelet or endothelial activation, inflammation and coagulation were altered. RhMCP-1 is a highly selective chemoattractant for monocytes in humans. The Duffy antigen only minimally alters the pharmacokinetics of rhMCP-1 for doses up to 2 μg/kg.

3033 Background: JTX-2011 is an agonist monoclonal antibody that targets ICOS, Inducible CO-Stimulator of T cells. A dual mechanism of action is intended to activate antigen-specific CD4 T effector cells and selectively deplete intratumoral T regulatory cells. JTX-2011 is equally potent across human, rodent, and non-human primate species. Methods: A quantitative systems pharmacology (QSP) model describing target binding by JTX-2011 and target mediated drug disposition in blood, tumor and non-tumor tissues was based on preclinical potency and non-linear PK data across species. The model was translated to predict PK and target engagement (TE) in humans to facilitate dose selection. The QSP model predicts > 95% TE for 21 days at the top planned dose. We present safety and actual/predicted PK from a Phase 1 study of JTX-2011 alone (Part A) and safety in combination with nivo (Part B). Results: 25 subjects have been dosed, 19 in 4 cohorts of JTX-2011 alone at .003, .01, .03, and .1 mg/kg IV q 21 days, and 6 in 2 cohorts of JTX-2011 .01 mg/kg and .03 mg/kg IV plus nivo 240 mg IV q21 days. Safety data from ≥ 1 cycle is available for 12 subjects in Part A (7 ≥ 3 cycles), and 3 in Part B (all ≥ 3 cycles). PK data is available for cycle 1 of Part A. Mean age (±SD) is 60 (±10.6). Mean prior systemic therapies is > 5 (range 1-11). Tumor types include endometrial, triple negative breast, melanoma, lung, pancreatic and colorectal cancers. No dose limiting toxicities have been reported. 3 Grade 3 adverse events (AEs) were reported in 2 Part A subjects: anemia and hypoxia (unrelated SAE) at .003 mg/kg and JTX-2011 related diarrhea at .1 mg/kg. Grade 1-2 AEs in ≥2 subjects are chills, pyrexia, neck pain, dizziness, and nausea. 5 subjects had JTX-2011 related Grade 1-2 infusion reactions up to 6 hours post infusion. Non-linear exposure increase was observed. While PK at lower doses is consistent with model predictions, AUC and t1/2at 0.03 and 0.1 mg/kg doses are higher than predicted, suggesting higher than predicted TE. Conclusions: JTX-2011 has been well tolerated up to 0.1 mg/kg and with nivo at .01 mg/kg IV q 21 days. Greater than linear exposure increase was observed and TE may be higher than QSP model prediction. Clinical trial information: NCT02904226.

BACKGROUND: The inflammatory response in patients with seasonal allergic rhinitis (SAR) is partly mediated by the prostaglandin D2 receptor chemoattractant receptor homologous molecule on TH2 cells (CRTH2). OBJECTIVE: We sought to investigate the efficacy and safety of the oral CRTH2 antagonist BI 671800 (50, 200, and 400 mg twice daily), fluticasone propionate nasal spray (200 mg once daily), or oral montelukast (10 mg once daily) administered for 2 weeks in patients with SAR. METHODS: In this randomized, double-blind, placebo-controlled, partial-crossover study, participants aged 18 to 65 years with a positive skin prick test to Dactylis glomerata pollen were exposed to out-of-season allergen in the environmental challenge chamber for 6 hours. The primary efficacy variable was the total nasal symptom score assessed as the area under the curve (AUC)0-6h. RESULTS: In total, 146 patients (63.7% male; mean age, 36.1 years) were randomized. The adjusted mean total nasal symptom score AUC0-6h was significantly reduced versus placebo with 200 mg of BI 671800 (absolute difference, -0.85; percentage difference, -17%; P = .0026), montelukast (absolute difference, -0.74; percentage difference, -15%; P = .0115), and fluticasone propionate (absolute difference, -1.64; percentage difference, -33%; P < .0001). Compared with placebo, BI 671800 significantly reduced nasal eosinophil values (P < .05 for all doses), significantly inhibited nasal inflammatory cytokine levels (IL-4 and eotaxin, P < .05; 200 mg twice daily), and induced a dose-related reduction in ex vivo prostaglandin D2-mediated eosinophil shape change. CONCLUSION: Two hundred milligrams of BI 671800 twice daily demonstrated efficacy in treating SAR symptoms induced by environmental challenge chamber allergen exposure and had a favorable safety profile.

The alpha 1-adrenoceptor antagonists doxazosin and terazosin and the 5 alpha-reductase inhibitor finasteride are used in the treatment of benign prostatic hyperplasia. The aim of this study was to assess the potential pharmacokinetic interaction of doxazosin or terazosin when coadministered with finasteride. This was a randomized, placebo-controlled, multi-center study. Ninety healthy men were assigned to one of six treatment groups: doxazosin; doxazosin plus finasteride; terazosin; terazosin plus finasteride; placebo; and placebo plus finasteride. Plasma concentrations, maximum plasma concentration (Cmax), time to maximum concentration (tmax), and area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) of doxazosin, terazosin, and finasteride were determined. Ratios of Cmax and AUC for doxazosin and terazosin were not significantly altered by coadministration with finasteride. The Cmax and AUC0-24 of finasteride were not significantly altered by coadministration with doxazosin. However, Cmax and AUC0-24 of finasteride were significantly higher after coadministration with terazosin. There is no statistically significant pharmacokinetic interaction between finasteride and doxazosin; however, there is a statistically significant interaction between finasteride and terazosin, which affects the pharmacokinetics of finasteride but not those of terazosin. The clinical significance of this interaction remains to be determined.

Background Blocking the CD40-CD40L pathway may be a new emergent treatment for patients with RA. BI 655064 is a humanized, purely antagonistic anti-CD40 monoclonal antibody. In healthy volunteers, BI 655064 was well tolerated in doses up to 240 mg q1w s.c. for 4 weeks. Doses ≥120 mg resulted in persistent >90% CD40 receptor occupancy and >90% inhibition of CD40L-induced CD54 upregulation. Objectives BI 655064 was investigated in RA patients with prior inadequate response (IR) to a stable dose of MTX at ≥15 mg. Methods In this double-blind, randomized trial, RA patients (n=67) were treated with either 120 mg BI 655064 or placebo q1w (2:1, respectively) for 12 weeks as add-on to MTX. Patients were stratified based on region (Eastern Europe vs. Western Europe/New Zealand). Inclusion criteria were ≥6 swollen and ≥6 tender joints, CRP ≥8 mg/L or ESR ≥28 mm/1h. The primary efficacy endpoint was ACR20 response at week 12. Results Baseline variables of the 2 groups were comparable except mean baseline CRP, which was substantially lower in patients treated with BI 655064 (9.8 mg/L) vs. placebo (23.6 mg/L). Treatment was prematurely discontinued by 4 patients (9.1%) in the BI 655064 group and 4 (17.4%) in the placebo group. Adverse events (AE) were reported in 65.9% of BI 655064-treated patients vs. 78.3% of placebo-treated patients. Two SAEs were reported in each group, neither was considered drug-related. The most frequently reported AEs were nasopharyngitis (BI 655064: 13.6%, placebo: 21.7%) and headache (BI 655064: 6.8%, placebo: 13.0%). There were no relevant changes in safety-related laboratory parameters. Efficacy results of all patients (FAS), including a subgroup of patients with CRP > median (7.5 mg/L; upper limit of normal: 6.0 mg/L), are listed in the table. All 6 patients who had previously received anti-TNF therapy were in the BI 655064 group; 4 achieved an ACR20 and 2 achieved an ACR50 response. There was a median decrease in ESR and total rheumatoid factor in the BI 655064-treated group by 16 mm/h and 81.5 IU/mL, respectively, compared with a decrease of 9 mm/h and 0.2 IU/mL in the placebo group. Conclusions In this relatively small proof-of-clinical-concept trial, treatment of MTX IR RA patients with BI 655064 did not indicate a relevant safety concern and showed moderate efficacy, which might have been impacted by the relatively high placebo response rate and the imbalance in baseline CRP. Disclosure of Interest S. Daniluk: None declared, R. Ptaszynski: None declared, U. Mueller-Ladner Consultant for: Boehringer Ingelheim, A. Petrikova: None declared, H. Kellner: None declared, E. Dokoupilova: None declared, B. Kwiatkowska: None declared, R. Alten Grant/research support from: Boehringer Ingelheim, C. Schwabe Grant/research support from: Boehringer Ingelheim, B. Rosenstock Employee of: Boehringer Ingelheim, T. Doan Employee of: Boehringer Ingelheim, R. Thiedmann Employee of: Boehringer Ingelheim, F. Fleischer Employee of: Boehringer Ingelheim, J. Hilbert Employee of: Boehringer Ingelheim, S. Visvanathan Employee of: Boehringer Ingelheim, S. Padula Employee of: Boehringer Ingelheim, J. Steffgen Employee of: Boehringer-Ingelheim

Background The CD40-CD40L pathway may play a major role in autoimmune disorders like rheumatoid arthritis (RA). Blocking this pathway may be a promising new treatment for RA-patients. BI 655064 is a novel humanized antagonistic anti-CD40 monoclonal antibody, free of agonistic activity and without antibody-dependent cellular- or complement-dependent cytotoxicity. BI 655064 binds human CD40 on B cells in whole blood with an EC 90 of 6.85±0.74 nM. Objectives BI 655064 was investigated in healthy volunteers to assess safety, tolerability, PK and PD after single and multiple dosing. Methods In a single-blinded randomized, placebo-controlled trial in healthy subjects, BI 655064 was administered to 72 male subjects in increasing single doses of 0.2-120 mg i.v. and 40-120 mg s.c. A double-blinded multiple rising dose study was conducted in 40 male and female subjects at doses of 80-240 mg q1w s.c. for 4 weeks. Blood samples were analyzed for PK, CD40-receptor occupancy (RO) and inhibition of CD40L-induced CD54-upregulation throughout the entire trial duration. Results All doses of BI 655064 were well tolerated in both studies. There was no-drug related serious adverse event (AE) or significant AE reported. Reported AEs were mainly of mild intensity and did not show a dose-relationship. There was no significant difference in the total number of subjects with AE [BI 655064: 47/86 (54%) vs. placebo: 16/26 (61%)] or category of reported AEs between subjects treated with BI 655064 or placebo (combined data from both studies). The most frequently reported AEs were headache (BI 655064 23% vs. placebo 19%) and upper respiratory tract infection (BI 655064 13% vs placebo 12%) in both studies (combined data). There was no evidence of thromboembolism or bleeding, no hypersensitivity reaction, no cytokine release and no relevant change in safety laboratory tests including coagulation parameters. BI 655064 plasma exposure increased in a supra-proportional manner indicating target mediated drug clearance with a terminal half-life ranging between 6 and 13 days. At single i.v. doses of 20 mg and higher, there was >90% RO and >90% inhibition of CD40L-induced CD54 upregulation for 24 hours after dosing. Single doses of 120 mg i.v. or s.c resulted in >90% RO and >90% inhibition of CD54 upregulation for at least one week. After multiple dosing, persistent >90% RO and >90% inhibition of CD40L-induced CD54 upregulation was maintained for the entire treatment period and for 3 weeks after the last dose for all doses of 120 mg q1w and above. Conclusions Early trials with BI 655064 show a favorable clinical safety profile and high potential to block the CD40-CD40L pathway supporting clinical trials with BI 655064 in RA-patients. Disclosure of Interest C. Schwabe Employee of: Auckland Clinical Studies, F. Wagner Employee of: Charite Research Institute, I. Filler Employee of: Charite Research Institute, M. Albulescu Employee of: Boehringer-Ingelheim, P. Rose Employee of: Boehringer-Ingelheim, B. Emerson Employee of: Boehringer-Ingelheim, T. Doan Employee of: Boehringer-Ingelheim, B. Rosenstock Employee of: Boehringer-Ingelheim, D. Joseph Employee of: Boehringer-Ingelheim, J. Hilbert Employee of: Boehringer-Ingelheim, C. Scholch Employee of: Boehringer-Ingelheim, J. Habeck Employee of: Boehringer-Ingelheim, R. Thiedmann Employee of: Boehringer-Ingelheim, S. Padula Employee of: Boehringer-Ingelheim, J. Steffgen Employee of: Boehringer-Ingelheim

Background Monocytes and macrophages play a major role in the pathogenesis of rheumatoid arthritis (RA). The chemokine receptor CCR1 regulates migration of these cells to synovial tissue and the bone. It is expected that sustained full antagonism of CCR1 will block trafficking of monocytes to the site of inflammation and will block the upregulation of cytokines, adhesion molecules and MMPs to slow the progression of joint damage in RA. Objectives This clinical study investigated safety, tolerability, pharmacokinetics and pharmacodynamics of the novel selective CCR1 antagonist BI 638683. Methods In a randomised, blinded, placebo-controlled trial, single rising doses from 1 to 700 mg BI 638683 or placebo were administered to 63 young healthy male volunteers (mean age 32 ± 9 years; mean BMI was 24.7 ± 2.4 kg/m 2 ). Subjects were randomised in a 6:2 ratio to active or placebo per group. Two distinct mechanistic blood-based biomarker assays were used to establish a PK/PD relationship: 1. inhibition of MIP1α-induced CCR1 receptor internalization (RI) and 2. inhibition of RANTES-induced CCR1 dependent gene expression of CCL2 , CLEC5A , RAB7B and PPARG Results All doses of BI 638683 were well tolerated. There were no serious adverse events (AE) and no AEs of severe intensity. There was no dose-relationship of AEs and no difference in the number or category of reported AEs in subjects treated with BI 638683 (7/47; 14.9%) compared to those treated with placebo (3/16; 18.8%). The most frequent AEs were GI disorders which were reported in 5/47 (10.6%) subjects treated with BI 638683 and 2/16 (12.5%) subjects treated with placebo. Only one event of nausea in the 700g mg dose group was rated as drug related. Plasma exposure of BI 638683 increased in a near dose-linear fashion, with a terminal t½ of 5-15 h. Two hours after dosing (the pharmacokinetic t max ), a dose of 150 mg BI 638683 inhibited RI by approximately 90%. The percentage of inhibition was directly related to the dose of BI 638683. At the 700 mg dose, an 83% inhibition of RI was measured at 24 h after dosing. Maximal inhibition of mRNA expression of the 4 CCR1 dependent marker genes was reached with a dose of 75 mg BI 638683 at the t max . 24 h after dosing, ≥90% mean inhibition was still maintained for CCL2 and PPARG mRNAs by doses of 300 mg and higher, and for RAB7B mRNA by doses of 500 mg and higher. For CLEC5A , inhibition of 84% and 91% was achieved for the 500 and 700 mg dose, respectively. Conclusions Treatment with BI 636683 was well tolerated. The biomarker assays indicated substantial inhibition and demonstrated proof of mechanism for BI 638683 as a CCR1 inhibitor in early stage of clinical development, and the PK/PD data using these biomarkers can be used to determine appropriate dosing for this compound. Disclosure of Interest : P. Baum Employee of: Boehringer-Ingelheim, C. Schoelch Employee of: Boehringer-Ingelheim, H. Zimdahl-Gelling Employee of: Boehringer-Ingelheim, M. Brown Employee of: Boehringer-Ingelheim, D. Webb Employee of: Boehringer-Ingelheim, S. Padula Employee of: Boehringer-Ingelheim, J. Hilbert Employee of: Boehringer-Ingelheim, T. Giessmann Employee of: Boehringer-Ingelheim, J. Steffgen Employee of: Boehringer-Ingelheim DOI 10.1136/annrheumdis-2014-eular.2352

OBJECTIVE: To evaluate the potential pharmacokinetic interaction between 2 × 150 mg fluconazole administered once weekly and an oral contraceptive (OC) containing ethinyl estradiol and norethindrone. METHODS: A placebo-controlled, double-masked, randomized, two-way crossover study was used to investigate the pharmacokinetic interaction between 300 mg fluconazole once weekly and the OC Ortho Novum 7/7/7 (Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ) in 26 healthy women, 18–36 years old. In the first cycle (28 days), subjects received OC only. In the second cycle, subjects were assigned randomly to receive OC-fluconazole or OC-placebo. In the third cycle, subjects were crossed over to the opposite treatment. RESULTS: Data for 21 subjects who completed the study were included in the pharmacokinetic analysis; data for all 26 subjects were included in the safety analysis (26 OC only; 24 OC-fluconazole; 23 OC-placebo). Treatment with OC-fluconazole resulted in small but statistically significant increases in 0–24 hour area under the plasma concentration-time curve (AUC 0–24 ) for both ethinyl estradiol (mean 24%, 95% confidence interval [CI] 18%, 31%) and norethindrone (mean 13%, 95% CI 8%, 18%) as compared with treatment with OC-placebo. Ethinyl estradiol maximum plasma concentration (C max ) was slightly (mean 8%, 95% CI 2%, 15%) though statistically significantly higher for OC-fluconazole treatment as compared with OC-placebo treatment. Norethindrone C max was not different (95% CI −6%, 11%) between the two treatment groups. No adverse events related to treatment were seen in the fluconazole treatment group. CONCLUSION: The concomitant administration of 300 mg fluconazole once weekly, twice the recommended dose for vaginal candidiasis, to women using OCs results in a slight increase in OC concentrations. Therefore, it appears that there is no threat of contraceptive failure because of concomitant fluconazole administration.

Background: Fluconazole has proven to be safe and effective for a variety of superficial and systemic fungal infections. Preliminary analysis of extensive Phase III studies suggests that it is very effective for the treatment of onychomycosis. Its pharmacokinetic properties, including low molecular weight and high water-solubility, suggest a unique ability to penetrate the nail. This feature is likely to account in part for fluconazole's effectiveness in the treatment of onychomycosis. Objective: Determinations of plasma and fingernail concentrations of fluconazole were performed as part of a larger study comparing the safety and efficacy of once-weekly fluconazole (150, 300, and 450 mg) to placebo in the treatment of distal subungual onychomycosis of the fingernails caused by dermatophytes. The relationship between fluconazole concentrations and efficacy was also examined. Methods: Pharmacokinetic studies were performed by means of plasma and fingernail samples from 133 patients, a subset of 349 patients participating in a double-blind, placebo-controlled clinical trial of fluconazole administered in once-weekly doses of 150, 300, or 450 mg until cure of onychomycosis or for a maximum of 9 months. Blood and fingernail samples for pharmacokinetic analysis were taken at baseline, at week 2, and at monthly intervals during the treatment phase of the study. Patients considered clinically cured or improved also participated in a 6-month follow-up study. During this phase, patients were monitored and samples taken every 2 months. Results: Significant amounts of fluconazole were detected in the earliest fingernail samples taken (after 2 weeks of treatment). After two weekly doses, 30% to 33% of steady-state concentrations had been achieved in healthy nails and 22% to 29% in affected nails. Steady state was achieved in 3 to 5 months. Fluconazole concentration in nails as well as plasma followed dose-proportional pharmacokinetics. Nail:plasma ratios in affected nails were 0.4 to 0.6 at 2 weeks and 1.7 to 1.8 at 6 months. Fluconazole concentrations fell slowly after drug discontinuation and were still detectable 4 months after end of treatment. A statistically significant correlation was found between steady-state concentration and clinical and global outcomes. Conclusion: Fluconazole rapidly penetrates the fingernail, where it is retained at detectable levels for at least 4 months after drug discontinuation. A significant correlation exists between fluconazole concentration in the fingernails and clinical and global outcomes. (J Am Acad Dermatol 1998;38:S110-6.)

Background: Preliminary clinical data suggest that fluconazole is effective in the treatment of patients with onychomycosis. To design optimum dosage regimens, a better understanding of fluconazole's distribution into and elimination from nails is needed. Objective: The purpose of this study was to determine plasma and toenail concentrations of fluconazole. Methods: In this multicenter, randomized, double-blind investigation, fluconazole (150 mg, 300 mg, or 450 mg) or matching placebo was administered once a week for a maximum of 12 months to patients with onychomycosis of the toenail. A total of 151 subjects participated in the pharmacokinetic assessment. Blood samples and distal toenail clippings from both affected and healthy nails were obtained for fluconazole concentration determinations at baseline, at the 2-week visit, at each monthly visit until the end of treatment, and then at 2, 4, and 6 months (nail samples only at the latter two) after fluconazole was discontinued. Results: Fluconazole was detected in healthy and affected nails at the 2-week assessment in nearly all subjects. The median time to reach steady-state fluconazole concentrations in healthy nails was 4 to 5 months in the three fluconazole dose groups. In affected nails, steady-state fluconazole concentrations were achieved more slowly, with a median time of 6 to 7 months. At the 8-month assessment, affected toenail fluconazole concentrations were higher than corresponding plasma fluconazole concentrations, with ratios of 1.31 to 1.50 in the three active treatment groups. Toenail concentrations of fluconazole declined slowly after treatment was discontinued, with elimination half-lives of 2.5, 2.4, and 3.7 months for the 150, 300, and 450 mg doses, respectively. Measurable fluconazole concentrations were still present in toenails at 6 months after treatment in most subjects. Conclusion: Fluconazole penetrates healthy and diseased nails rapidly, yielding detectable concentrations after two weekly doses. Once it penetrates nail, fluconazole persists for up to 6 months or longer after therapy is stopped. These favorable pharmacokinetic characteristics support a once-weekly fluconazole dosage regimen for the treatment of patients with onychomycosis. (J Am Acad Dermatol 1998;38:S103-9.)

The thermally induced structural evolution of hydrogenated amorphous carbon (a-C:H) films was investigated in situ by X-ray photoelectron spectroscopy for annealing temperatures up to 500 °C. A model for the conversion of sp3- to sp2-hybridized carbon in a-C:H vs. temperature and time was developed and applied to determine the ranges of activation energies for the thermally activated processes occurring. The energies are consistent with ordering and clustering of sp2 carbon, scission of sp3 carbon-hydrogen bonds and formation of sp2 carbon, and direct transformation of sp3- to sp2-hybridized carbon.