Tolerability and Safety of Large-Volume Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 10% Administered with or without Dose Ramp-Up: A Phase 1 Study in Healthy Participants.

PURPOSE: Facilitated subcutaneous immunoglobulin (fSCIG; immune globulin infusion 10% [human] with recombinant human hyaluronidase [rHuPH20]) permits high-volume subcutaneous immunoglobulin (SCIG) infusion, shorter infusion times and reduced dosing frequency relative to conventional SCIG. It is initiated by gradually increasing infusion volumes over time (dose ramp-up) to achieve target dose level (TDL). Whether ramp-up strategies have tolerability or safety advantages over direct initiation at full TDL has not been evaluated clinically. METHODS: This phase 1 open-label study assessed tolerability and safety of fSCIG 10% with accelerated or no ramp-up compared with conventional ramp-up in healthy adults (NCT04578535). Participants were assigned to one of the three ramp-up arms to achieve TDLs of 0.4 or 1.0 g/kg/infusion. The primary endpoint was the proportion of infusions completed without interruption or infusion rate reduction owing to treatment-emergent adverse events (TEAEs). Safety was assessed as a secondary endpoint. RESULTS: Of 51 participants enrolled, 50 (98.0%) tolerated all fSCIG 10% infusions initiated (n = 174). Infusion rate was reduced in one participant owing to headache in the 0.4 g/kg/infusion conventional ramp-up arm. Study discontinuations were higher in the no ramp-up arm (70%) versus the conventional (0%) and accelerated (22%) arms at the 1.0 g/kg/infusion TDL. Safety outcomes did not substantially differ between treatment arms. CONCLUSION: The favorable tolerability and safety profiles of fSCIG 10% in healthy participants support initiating treatment with fSCIG 10% with accelerated ramp-up at TDLs up to 1.0 g/kg. Data support no ramp-up at TDLs close to 0.4 g/kg but additional data are needed for higher doses.

Bidimensional Spectroelectrochemistry with Tunable Thin-Layer Thickness.

Bidimensional spectroelectrochemistry (Bidim-SEC) is an instrumental technique that provides operando UV/vis absorption information on electrochemical processes from two different points of view, using concomitantly a parallel and a normal optical configuration. The parallel configuration provides information about chemical species present in the diffusion layer, meanwhile the normal arrangement supplies information about changes occurring both in the diffusion layer and, mainly, on the electrode surface. The choice of a suitable cell to perform Bidim-SEC experiments is critical, especially while working under a thin-layer regime. So far, most of the proposed Bidim-SEC cells rely on the use of spacers to define the thin-layer thickness, which leads to working with constant thickness values. Herein, we propose a novel Bidim-SEC cell that enables easy-to-use micrometric control of the thin-layer thickness using a piezoelectric positioner. This device can be used for the study of complex interfacial systems and also to easily measure the key parameters of an electrochemical process. As a proof of concept, the study of the roughening of a gold electrode in KCl medium is performed, identifying key steps in the passivation and nanoparticle generation on the gold surface.

A Phase 1 Open-Label Study to Assess the Tolerability, Safety, and Immunogenicity of Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 20% in Healthy Adults.

PURPOSE: Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 20% will allow reduced infusion volumes and frequency versus existing subcutaneous therapies such as fSCIG 10% and conventional subcutaneous immunoglobulin 20%, respectively. We assessed the tolerability, safety, and immunogenicity of warmed and unwarmed fSCIG 20%. METHODS: This phase 1, single-dose, open-label, three-arm study enrolled healthy adults aged 19-50 years (inclusive) at a single US center (NCT05059977). Post-screening, participants received a single fSCIG 20% dose comprising recombinant human hyaluronidase and varying doses of in-line warmed or unwarmed immunoglobulin G (IgG) during a 4-day treatment period in a sentinel and sequential dosing design (treatment arm 1, warmed IgG 20% 0.4 g/kg; treatment arm 2, warmed IgG 20% 1.0 g/kg; treatment arm 3, unwarmed IgG 20% 1.0 g/kg). Participants were followed for 12 (± 1) weeks post-infusion. The primary endpoint was tolerability ("tolerable" infusions were not interrupted, stopped, or reduced in rate owing to fSCIG 20%-related treatment-emergent adverse events (TEAEs)). Secondary endpoints included occurrence of TEAEs. RESULTS: Overall, 24 participants were included, 8 per treatment arm (mean age 39.0 years, 54.2% men). All participants tolerated the infusions. All TEAEs were mild (107 events, in all participants), and all participants experienced fSCIG 20%-related (105 events) and local (102 events) TEAEs. Infusion site erythema and infusion site swelling were most frequently reported. No serious TEAEs occurred, and no participants discontinued the study owing to TEAEs. CONCLUSION: fSCIG 20% was well-tolerated with a favorable safety profile in healthy adults. Future studies will evaluate fSCIG 20% in primary immunodeficiency diseases. Trial registration number (ClinicalTrials.gov): NCT05059977 (registered 28 September 2021).

Photoactive Au@MoS2 Micromotors for Dynamic Surface-Enhanced Raman Spectroscopy Sensing.

Photophoretic Au@MoS2 micromotors are used as smart mobile substrates for dynamic surface-enhanced Raman spectroscopy (SERS) sensing. The photophoretic capabilities and swarming-like propulsion of the micromotors allow for their schooling and accumulation in the measuring spot, increasing the density of SERS-active gold nanoparticles for Raman mapping and, simultaneously, the preconcentration of the target analyte. The generation of "hot-microflake spots" directly in the Raman irradiation point results in a 15-18-fold enhancement in the detection of crystal violet without the requirement for additional external sources for propulsion. Moreover, the reproducible collective micromotor motion does not depend on the exact position of the laser spot concerning individual micromotors, which greatly simplifies the experimental setup, avoiding the requirements of sophisticated equipment. The strategy was further applied for the detection of malachite green and paraquat with a good signal enhancement. The new on-the-move-based SERS strategy holds great promise for on-site detection with portable instrumentation in a myriad of environmental monitoring and clinical applications.

Fe-MOF Catalytic Nanoarchitectonic toward Electrochemical Ammonia Production.

Electrochemical reduction of nitrate into ammonia has lately been identified as one among the promising solutions to address the challenges triggered by the growing global energy demand. Exploring newer electrocatalyst materials is vital to make this process effective and feasible. Recently, metal-organic framework (MOF)-based catalysts are being well investigated for electrocatalytic ammonia synthesis, accounting for their enhanced structural and compositional integrity during catalytic reduction reactions. In this study, we investigate the ability of the PCN-250-Fe3 MOF toward ammonia production in its pristine and activated forms. The activated MOF catalyst delivered a faradaic efficiency of about 90% at -1 V vs RHE and a yield rate of 2.5 × 10-4 mol cm-2 h-1, while the pristine catalyst delivered a 60% faradaic efficiency at the same potential. Theoretical studies further provide insights into the nitrate reduction reaction mechanism catalyzed by the PCN-250-Fe3 MOF catalyst. In short, simpler and cost-effective strategies such as pretreatment of electrocatalysts have an upper hand in aggravating the intrinsic material properties, for catalytic applications, when compared to conventional material modification approaches.

Raman, UV-Vis Absorption, and Fluorescence Spectroelectrochemistry for Studying the Enhancement of the Raman Scattering Using Nanocrystals Activated by Metal Cations.

Raman signal enhancement is fundamental to develop different analytical tools for chemical analysis, interface reaction studies, or new materials characterization, among others. Thus, phenomena such as surface-enhanced Raman scattering (SERS) have been used for decades to increase the sensitivity of Raman spectroscopy, leading to a huge development of this field. Recently, an alternative method to SERS for the amplification of Raman signals has been reported. This method, known as electrochemical surface oxidation-enhanced Raman scattering (EC-SOERS), has been experimentally described. However, to date, it has not yet been fully understood. In this work, new experimental data that clarify the origin of the Raman enhancement in SOERS are provided. The use of a complete and unique set of combined spectroelectrochemistry techniques, including time-resolved operando UV-vis absorption, fluorescence, and Raman spectroelectrochemistry, reveals that such enhancement is related to the generation of dielectric or semiconductor nanocrystals on the surface of the electrode and that the interaction between the target molecule and the dielectric substrate is mediated by metal cations. According to these results, the interaction metal electrode-nanocrystal-metal cation-molecule is proposed as being responsible for the Raman enhancement in Ag and Cu substrates. Elucidation of the origin of the Raman enhancement will help to promote the rational design of SOERS substrates as an attractive alternative to the well-known SERS phenomenon.

A phase I, open-label, single-dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib.

Futibatinib is a covalently binding FGFR1-4 inhibitor that received US Food and Drug Administration approval for the treatment of patients with previously treated, advanced intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions/rearrangements. This phase I trial evaluated the pharmacokinetics (PKs), safety, and tolerability of futibatinib in subjects with impaired hepatic function and matched healthy volunteers. Twenty-two subjects with hepatic impairment (8 mild [Child-Pugh 5-6], 8 moderate [7-9], and 6 severe [10-15]) and 16 matched healthy control subjects received a single oral dose of futibatinib 20 mg. Futibatinib PKs were compared between subjects with mild/moderate/severe hepatic impairment and each corresponding control cohort and the overall control cohort. Relationships between futibatinib PKs and Child-Pugh scores and liver function tests were examined via scatter/regression plots. Compared with matched controls, the area under the plasma concentration-time curve from time zero to infinity increased by 21%/20%/18% and the maximum plasma concentration (Cmax ) increased by 43%/15%/10% in subjects with mild/moderate/severe hepatic impairment, respectively. Changes were not considered clinically relevant: geometric mean ratios were within 80%-125%, except for Cmax in subjects with mild hepatic impairment (143%). No obvious trends were observed among futibatinib PK parameters versus Child-Pugh scores, bilirubin, albumin, international normalized ratio, and aspartate aminotransferase (all p > 0.05). Futibatinib was well-tolerated, with only four grade 1 treatment-emergent adverse events (mild hepatic impairment = 2 and control = 2). The results demonstrate that futibatinib dose adjustments due to mild/moderate/severe hepatic impairment are not necessary in patients receiving futibatinib 20 mg daily.

Bioequivalence Studies of Sildenafil Citrate Orodispersible Film Administered with and without Water vs ViagraⓇ Film-Coated Tablets in Healthy Male Volunteers.

Background: Orodispersible film (ODF) formulation offers ease of use, convenience of administration, and other advantages, especially for patients who have difficulty in swallowing or are on liquid restriction compared with conventional oral formulations for the treatment of erectile dysfunction. Objectives: These studies compared the bioequivalence of 50 mg sildenafil citrate ODF formulation (test drug) with the marketed 50 mg sildenafil citrate film-coated tablet (FCT) (ViagraⓇ; Pfizer, New York, NY) (reference drug), with and without water in 2 randomized cross-over studies. Methods: Two randomized cross-over studies were conducted. The first study explored the bioequivalence of test drug administered with and without water compared with the reference drug with water. The second study investigated the bioequivalence of test drug, without water, compared with the reference drug with water. Forty-two and 80 healthy male volunteers were recruited in the first and second study, respectively. All volunteers fasted for 10 hours pre-dose. A 1-day washout period between doses was observed. Blood samples were collected at both before (up to 120 minutes before dosing) and after dosing (at different intervals up to 14 hours) stages. Statistical analyses on pharmacokinetic parameters were performed. Safety and tolerability for both the formulations were evaluated. Results: In the first study, bioequivalence was demonstrated for sildenafil citrate ODF administered with water when compared with the ViagraⓇ FCT. The ratios of adjusted geometric means (90% confidence interval (CI)) were maximum plasma concentration: 1.02 (94.91-108.78) and area under the plasma concentration-time curve: 1.09 (104.49-113.21) for sildenafil citrate ODF administered with water vs ViagraⓇ FCT. These ratios were within the bioequivalence acceptance range of 80% to 125%, indicating that the bioequivalence criteria were met. The pharmacokinetic parameters for the second study also showed bioequivalence for sildenafil citrate ODF (without water) compared with ViagraⓇ FCT. The ratios of adjusted geometric means (90% CI) were maximum plasma concentration: 1.02 (95.47-109.36) and area under the plasma concentration-time curve: 1.06 (103.42-108.40) for sildenafil citrate ODF administered without water vs ViagraⓇ FCT. Adverse events in both the studies occurred at similar rates for the 2 formulations and were mild in intensity. Conclusions: These results suggest that the new ODF formulation can be used interchangeably with the marketed FCT formulation. Sildenafil citrate ODF administered with and without water met bioequivalence criteria compared with ViagraⓇ FCT administered with water under fasted conditions in healthy adult male volunteers. The new ODF formulation can be used as a suitable alternative to the conventional oral solid dosage form.

Simultaneous Scanning Electrochemical Microscopy and UV-Vis Absorption Spectroelectrochemistry.

The combination of instrumental techniques allows obtaining precise and reliable information about the reactions taking place at the electrode/solution interface. Although UV-Vis absorption spectroelectrochemistry (UV-Vis SEC) provides a molecular insight about the species involved in the electrode process, obtaining information about the redox state of the products generated in this process is not always accessible by this technique. In this sense, scanning electrochemical microscopy (SECM) has a clear advantage, since it provides additional information on the oxidation state of the intermediates/products. Therefore, the combination of these two techniques facilitates obtaining a more complete picture of the electrochemical reaction studied from two different points of view, but under exactly the same experimental conditions. In this work, the combination of UV-Vis SEC in parallel configuration and SECM is carried out for the first time. This new technique allows distinguishing between those species that are electrochemically active and, at the same time, exhibit changes in the UV-Vis absorption spectra during the electrochemical reaction. The new experimental setup is first validated using ferrocenemethanol as a standard probe, concomitantly obtaining spectroscopic and electrochemical information that accurately describes the oxidation process. Finally, the strength of this combined technique is demonstrated by studying the antioxidant activity of o-vanillin (o-HVa) in the presence of electrogenerated superoxide. The information extracted from the new UV-Vis SEC/SECM technique makes it possible to identify, beyond any doubt, not only the origin of the electrochemical signals recorded in the SECM tip but also to evaluate the antioxidant effect of o-HVa at different concentrations.

Safety and Pharmacokinetics of Islatravir in Individuals with Severe Renal Insufficiency.

Islatravir (MK-8591) is a high-potency reverse transcriptase translocation inhibitor in development for the treatment of HIV-1 infection. Data from preclinical and clinical studies suggest that ~30% to 60% of islatravir is excreted renally and that islatravir is not a substrate of renal transporters. To assess the impact of renal impairment on the pharmacokinetics of islatravir, an open-label phase 1 trial was conducted with individuals with severe renal insufficiency (RI). A single dose of islatravir 60 mg was administered orally to individuals with severe RI (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) and to healthy individuals without renal impairment (matched control group; eGFR ≥90 mL/min/1.73 m2). Safety and tolerability were assessed, and blood samples were collected to measure the pharmacokinetics of islatravir and its major metabolite 4'-ethynyl-2-fluoro-2'deoxyinosine (M4) in plasma, as well as active islatravir-triphosphate (TP) in peripheral blood mononuclear cells (PBMCs). Plasma islatravir and M4 area under the concentration-time curve from zero to infinity (AUC0-∞) were ~2-fold and ~5-fold higher, respectively, in participants with severe RI relative to controls, whereas islatravir-TP AUC0-∞ was ~1.5-fold higher in the RI group than in the control group. The half-lives of islatravir in plasma and islatravir-TP in PBMCs were longer in participants with severe RI than in controls. These findings are consistent with renal excretion playing a major role in islatravir elimination. A single oral dose of islatravir 60 mg was generally well tolerated. These data provide guidance regarding administration of islatravir in individuals with impaired renal function. (This study has been registered at ClinicalTrials.gov under registration no. NCT04303156.).

Electrodeposition of Molybdenum Disulfide (MoS2) Nanoparticles on Monocrystalline Silicon.

Molybdenum disulfide (MoS2) has attracted great attention for its unique chemical and physical properties. The applications of this transition metal dichalcogenide (TMDC) range from supercapacitors to dye-sensitized solar cells, Li-ion batteries and catalysis. This work opens new routes toward the use of electrodeposition as an easy, scalable and cost-effective technique to perform the coupling of Si with molybdenum disulfide. MoS2 deposits were obtained on n-Si (100) electrodes by electrochemical deposition protocols working at room temperature and pressure, as opposed to the traditional vacuum-based techniques. The samples were characterized by X-ray Photoelectron Spectroscopy (XPS), Scanning Electron Microscopy (SEM), Atomic Force Microscopy (AFM) and Rutherford Back Scattering (RBS).

Safety and immunogenicity of intramuscular, single-dose V590 (rVSV-SARS-CoV-2 Vaccine) in healthy adults: Results from a phase 1 randomised, double-blind, placebo-controlled, dose-ranging trial.

BACKGROUND: Vaccines against COVID-19 are needed to overcome challenges associated with mitigating the global pandemic. We report the safety and immunogenicity of V590, a live recombinant vesicular stomatitis virus-based COVID-19 vaccine candidate. METHODS: In this placebo-controlled, double-blind, three-part phase 1 study, healthy adults were randomised to receive a single intramuscular dose of vaccine or placebo. In Part 1, younger (18-54 years) and, in Part 2, older (≥55 years) adults seronegative for SARS-CoV-2 nucleocapsid received one of four V590 dose levels (5.00 × 105; 2.40 × 106; 1.15 × 107; or 5.55 × 107 plaque-forming units [pfu]) or placebo. In Part 3, a single V590 dose level (5.55 × 107 pfu) or placebo was administered to younger SARS-CoV-2 seropositive adults. Primary endpoints included adverse events (AEs) and for Parts 1 and 2 anti-SARS-CoV-2 serum neutralising antibody responses measured by 50% plaque reduction neutralisation (PRNT50) assay at Day 28. Registration NCT04569786 [P001-02]. FINDINGS: 232 participants were randomised and 219 completed the study. In seronegative participants, anti-SARS-CoV-2 spike-specific antibody responses to V590 were low and comparable to placebo across the lower dose levels. At the highest dose level (5.55 × 107 pfu), anti-SARS-CoV-2 spike-specific PRNT50 was 2.3-fold higher than placebo. The most frequently reported AEs were injection-site pain (38.4%), headache (15.1%) and fatigue (13.4%). INTERPRETATION: V590 was generally well-tolerated. However, Day 28 anti-SARS-Cov-2 spike-specific antibody responses in seronegative participants following a single intramuscular administration of V590 were not sufficient to warrant continued development. FUNDING: The study was funded by Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Can the Pediatric Early Warning Score (PEWS) Predict Hospital Length of Stay?

BACKGROUND: Limited studies have evaluated the utility of scoring systems in the pediatric emergency department (PED) and no studies have evaluated their ability to predict hospital length of stay (LOS) and the usage of Observation units (OUs). OBJECTIVE: To evaluate the utility of the Pediatric Early Warning Score (PEWS) in predicting LOS in pediatric patients and thus anticipate admission to an OU versus the pediatric ward. METHODS: A retrospective study of pediatric inpatients (0 to 18 years) at an inner-city community hospital between January 2014 and December 2014. Patients with psychiatric illness, non-medical reasons for hospital stay, and those not discharged to 'home' were excluded. Demographic data, PEWS in the ED, and LOS for each patient were recorded and analyzed. RESULTS: A total of 719 patients were analyzed. PEWS range was 0 to 8. The mean LOS was 56.8 hours for patients with PEWS 0-1 compared to 62.7 hours for patients with PEWS ≥2 (p=0.02). There was a significant difference in PEWS for LOS ≤24 and ≤36 hours in comparison to those with LOS >24 hours and >36 hours, respectively (p<0.001). Overall, the PEWS correlated with LOS (r=0.11, p=0.002). Age correlated inversely with LOS (r=-0.16, p<0.001), without correlation to PEWS (r=-0.002, p= 0.96). CONCLUSIONS:  PEWS correlated weakly with LOS. A statistically significant lower PEWS was observed for patients who had short stays (both ≤24 and ≤36 hours) in comparison to those requiring longer inpatient care. Therefore, the PEWS is a useful tool to predict LOS and aid ED physicians to determine disposition, although further prospective studies in centers with OUs would better characterize its ability to suggest admission to an OU compared to the wards.

Determination of uric acid in synthetic urine by using electrochemical surface oxidation enhanced Raman scattering.

In this work, a new and easy methodology to determine uric acid in relevant samples using Raman spectroelectrochemistry is presented. The spectroelectrochemistry experiment is based on the in-situ formation of a suitable substrate that enables the enhancement of the Raman signal of an analyte during the oxidation stage of a silver electrode. This phenomenon is known as electrochemical surface oxidation enhanced Raman scattering (EC-SOERS) and has proved to be useful in quantitative analysis using disposable screen printed electrodes. The successful combination of EC-SOERS with PARAFAC analysis allows the determination of uric acid in a relevant complex sample avoiding the use of standard addition method and without using a baseline correction, which simplifies the application of such methodology in routine analysis.

Safety and tolerability of subcutaneous sarilumab and intravenous tocilizumab in patients with rheumatoid arthritis.

OBJECTIVE: Safety and efficacy of mAbs blocking the IL-6 receptor have been established in RA. This is the first analysis examining safety and tolerability of sarilumab and tocilizumab administered as single or multiple doses in patients with RA within the same study. METHODS: In ASCERTAIN, patients were randomized 1: 1: 2 to 24 weeks' double-blind sarilumab 150 or 200 mg every 2 weeks s.c. or tocilizumab 4 mg/kg every 4 weeks i.v., increased to 8 mg/kg if clinically indicated. In Study 1309, patients were randomized 1: 1: 1: 1 to single-dose open-label sarilumab 150 or 200 mg s.c. or tocilizumab 4 or 8 mg/kg i.v. RESULTS: In ASCERTAIN, incidence of treatment-emergent adverse events was similar between sarilumab and tocilizumab. The most common treatment-emergent adverse events were the following: sarilumab: neutropenia [6 patients (12.2%) in the 150 mg group and 8 (15.7%) in the 200 mg group], nasopharyngitis [6 (12.2%) and 3 (5.9%)], and injection-site erythema [4 (8.2%) and 4 (7.8%)]; tocilizumab: accidental overdose [9 (8.8%)], upper respiratory tract infection [7 (6.9%)] and nausea [7 (6.9%)]. Laboratory changes in both studies included decreased neutrophils and platelets and increased transaminases and lipids. In Study 1309, incidence of absolute neutrophil count <1.0 giga/l was similar between sarilumab and tocilizumab, and occurred more frequently in the higher dose groups. No association between decrease in absolute neutrophil count and increased incidence of infection was observed in either study. CONCLUSION: No clinically meaningful differences in treatment-emergent adverse events were observed between sarilumab and tocilizumab. Laboratory changes with sarilumab were within the same range as those with tocilizumab. TRIAL REGISTRATION NUMBERS: ASCERTAIN (NCT01768572); Study 1309 (NCT02097524).

Effects of bimagrumab, an activin receptor type II inhibitor, on pituitary neurohormonal axes.

BACKGROUND: Bimagrumab is a human monoclonal antibody inhibitor of activin type II receptors (ActRII), with anabolic action on skeletal muscle mass by blocking binding of myostatin and other negative regulators of muscle growth. Bimagrumab is under evaluation for muscle wasting and associated functional loss in hip fracture and sarcopenia, and in obesity. Bimagrumab also blocks other endogenous ActRII ligands, such as activins, which act on the neurohormonal axes, pituitary, gonads and adrenal glands. AIM: To evaluate the effect of bimagrumab on the pituitary-gonadal and pituitary-adrenal axes in humans. METHODS: Healthy men and women, aged 55 to 75 years, received bimagrumab intravenously 10 mg/kg or placebo on Day 1 and Day 29. Pituitary-gonadal and pituitary-adrenal functions were evaluated with basal hormone measurement and standard gonadotropin-releasing hormone (GnRH) and adrenocorticotropic hormone (ACTH) stimulation tests at baseline, Week 8 and at the end of study (EOS)-Week 20. RESULTS: At Week 8, follicle-stimulating hormone (FSH) levels were reduced by 42.16 IU/L (P < .001) and luteinizing hormone (LH) levels were increased by 2.5 IU/L (P = .08) over placebo in response to bimagrumab in women but not in men. Effects that were reversible after bimagrumab was cleared. Gonadal and adrenal androgen levels were not affected by exposure to bimagrumab. CONCLUSION: Bimagrumab alters the function of pituitary gonadotroph cells, consistent with blockade of activin on local ActRII. This effect is reversible with clearance of bimagrumab. Bimagrumab did not impact gonadal and adrenal androgen secretion.

Preclinical Profile and Clinical Efficacy of a Novel Hepatitis C Virus NS5A Inhibitor, EDP-239.

EDP-239, a novel hepatitis C virus (HCV) inhibitor targeting nonstructural protein 5A (NS5A), has been investigated in vitro and in vivo EDP-239 is a potent, selective inhibitor with potency at picomolar to nanomolar concentrations against HCV genotypes 1 through 6. In the presence of human serum, the potency of EDP-239 was reduced by less than 4-fold. EDP-239 is additive to synergistic with other direct-acting antivirals (DAAs) or host-targeted antivirals (HTAs) in blocking HCV replication and suppresses the selection of resistance in vitro Furthermore, EDP-239 retains potency against known DAA- or HTA-resistant variants, with half-maximal effective concentrations (EC50s) equivalent to those for the wild type. In a phase I, single-ascending-dose, placebo-controlled clinical trial, EDP-239 demonstrated excellent pharmacokinetic properties that supported once daily dosing. A single 100-mg dose of EDP-239 resulted in reductions in HCV genotype 1a viral RNA of >3 log10 IU/ml within the first 48 h after dosing and reductions in genotype 1b viral RNA of >4-log10 IU/ml within 96 h. (This study has been registered at ClinicalTrials.gov under identifier NCT01856426.).

A First-in-Human Study To Assess the Safety and Pharmacokinetics of Monoclonal Antibodies against Human Cytomegalovirus in Healthy Volunteers.

Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the function of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. Here, we evaluated the safety, tolerability, and pharmacokinetics of a single intravenous dose of LJP538 or LJP539 or their combination in healthy volunteers. Adverse events and laboratory abnormalities occurred sporadically with similar incidence between antibody and placebo groups and without any apparent relationship to dose. No subject who received antibody developed a hypersensitivity, infusion-related reaction or anti-drug antibodies. After intravenous administration, both LJP538 and LJP539 demonstrated typical human IgG1 pharmacokinetic properties, with slow clearances, limited volumes of distribution, and long terminal half-lives. The pharmacokinetic parameters were linear and dose proportional for both antibodies across the 50-fold range of doses evaluated in the study. There was no apparent impact on pharmacokinetics when the antibodies were administered alone or in combination. CSJ148 and the individual monoclonal antibodies were safe and well tolerated, with pharmacokinetics as expected for human immunoglobulin.

Oxidation mechanism of formic acid on the bismuth adatom-modified Pt(111) surface.

In order to improve catalytic processes, elucidation of reaction mechanisms is essential. Here, supported by a combination of experimental and computational results, the oxidation mechanism of formic acid on Pt(111) electrodes modified by the incorporation of bismuth adatoms is revealed. In the proposed model, formic acid is first physisorbed on bismuth and then deprotonated and chemisorbed in formate form, also on bismuth, from which configuration the C-H bond is cleaved, on a neighbor Pt site, yielding CO2. It was found computationally that the activation energy for the C-H bond cleavage step is negligible, which was also verified experimentally.

Formic acid electrooxidation on thallium-decorated shape-controlled platinum nanoparticles: an improvement in electrocatalytic activity.

Thallium modified shape-controlled Pt nanoparticles were prepared and their electrocatalytic activity towards formic acid electrooxidation was evaluated in 0.5 M sulfuric acid. The electrochemical and in situ FTIR spectroscopic results show a remarkable improvement in the electrocatalytic activity, especially in the low potential region (around 0.1-0.2 V vs. RHE). Cubic Pt nanoparticles modified with Tl were found to be more active than the octahedral Pt ones in the entire range of Tl coverages and potential windows. In situ FTIR spectra indicate that the promotional effect produced by Tl results in the inhibition of the poisoning step leading to COads, thus improving the onset potential for the complete formic acid oxidation to CO2. Chronoamperometric experiments were also performed at 0.2 V to evaluate the stability of the electrocatalysts at constant potential. Finally, experiments with different concentrations of formic acid (0.05-1 M) were also carried out. In all cases, Tl-modified cubic Pt nanoparticles result to be the most active. All these facts reinforce the importance of controlling the surface structure of the electrocatalysts to optimize their electrocatalytic properties.