Hash and Physical Unclonable Function (PUF)-Based Mutual Authentication Mechanism.

The security of web applications in an enterprise is of paramount importance. To strengthen the security of applications, the identification and mitigation of vulnerabilities through appropriate countermeasures becomes imperative. The Open Web Application Security Project (OWASP) Top 10 API Security Risks, 2023 Edition, indicates the prominent vulnerabilities of API security risks. Broken authentication, however, is placed in second position with level-3 exploitability, level-2 prevalence, level-3 detectability, and level-3 technical impact. To mitigate this vulnerability, many mitigation strategies have been proposed by using the cryptographic primitives wherein two techniques, namely hashing and PUF, are used. Some of the proposals have integrated the concepts of hashing and PUF. However, the unnecessarily lengthy and complex mathematics used in these proposals makes them unsuitable for current API-based application scenarios. Therefore, in this paper, the authors propose a privacy-preserving authentication protocol that incorporates the capability of both mechanisms in an easy and low-complexity manner. In addition to overcoming existing limitations, the proposed protocol is tested to provide more security properties over existing schemes. Analysis of their performance has demonstrated that the proposed solutions are secure, efficient, practical, and effective for API-based web applications in an enterprise environment.

Potential beneficial effects of masupirdine (SUVN-502) on agitation/aggression and psychosis in patients with moderate Alzheimer's disease: Exploratory post hoc analyses.

OBJECTIVES: The effects of masupirdine on the neuropsychiatric symptoms were explored. METHODS: Masupirdine (SUVN-502) was evaluated for its effects on cognition in patients with moderate AD. The prespecified primary outcome showed no drug-placebo difference. Post hoc analyses of domains of the 12-item neuropsychiatric inventory scale were carried out. RESULTS: In a subgroup of patients (placebo, n = 57; masupirdine 50 mg, n = 53; masupirdine 100 mg, n = 48) with baseline agitation/aggression symptoms ≥1, a statistically significant reduction in agitation/aggression scores was observed in masupirdine 50 mg (95% confidence interval (CI), -1.9 to -0.5, p < 0.001) and masupirdine 100 mg (95% CI, -1.7 to -0.3, p = 0.007) treated arms at Week 13 in comparison to placebo and the effect was sustained for trial duration of 26 weeks in the masupirdine 50 mg treatment arm (95% CI, -2.3 to -0.8, p < 0.001). Similar observations were noted in the subgroup of patients (placebo, n = 29; masupirdine 50 mg, n = 30; masupirdine 100 mg, n = 21) with baseline agitation/aggression symptoms ≥3. In the subgroup of patients (placebo, n = 28; masupirdine 50 mg, n = 28; masupirdine 100 mg, n = 28) who had baseline psychosis symptoms and/or symptom emergence, a significant reduction in psychosis scores was observed in the masupirdine 50 mg (Week 4: 95% CI, -2.8 to -1.4, p < 0.001; Week 13: 95% CI, -3.3 to -1.3, p < 0.001) and masupirdine 100 mg (Week 4: 95% CI, -1.4 to 0, p = 0.046; Week 13: 95% CI, -1.9 to 0.1, p = 0.073) treatment arms in comparison to placebo. CONCLUSION: Further research is warranted to explore the potential beneficial effects of masupirdine on NPS.

Short-term toxicity study of 1-aminobenzotraizole, a CYP inhibitor, in Wistar rats.

1-Aminobenzotriazole (ABT) is a pan-specific, mechanism-based inhibitor of CYP P450 enzymes, often used as co-treatment to investigate the metabolism-dependent toxicity of drugs or chemicals. To assess the confounding effects of ABT in such kind of mechanistic studies, a repeated dose toxicity study with ABT following 7 days oral administration at 0, 25, 50 and 100 mg/kg/day was performed in Wistar rats (5 rats/sex/group). Wistar rat is selected as a model being one of the well characterized rodent species, widely used for toxicity and toxicokinetics studies. The standard parameters of general toxicity study viz. clinical signs, body weight, feed consumption, clinical, gross and histopathology were evaluated. The ABT was tolerated up to the highest tested dose of 100 mg/kg/day. No clinical signs, mortality or effect on feed consumption at any dose. Slight increase in body weight gain was noted in ABT treated females. Increased reticulocyte, and decreased triglycerides, BUN, A/G ratio and plasma potassium; increased weight of liver, kidneys, adrenals and thyroid was noted in ABT treated animals. Microscopically, hypertrophic findings were noted in liver, thyroid, adrenal glands, pituitary and uterus. Some of these changes were observed at as low as 25 mg/kg/day, therefore, NOEL could not be established. Based on this study, it is concluded that ABT is tolerable up to 100 mg/kg/day with some variations in clinical pathology, organ weight and histopathology; these changes should be considered during the assessment of any mechanistic study with ABT. Findings of this manuscript were presented at 58th meeting of the Society of Toxicology, Baltimore, 11 March 2019.

COVID-19 Testing and Diagnostics: A Review of Commercialized Technologies for Cost, Convenience and Quality of Tests.

Population-scale and rapid testing for SARS-CoV-2 continues to be a priority for several parts of the world. We revisit the in vitro technology platforms for COVID-19 testing and diagnostics-molecular tests and rapid antigen tests, serology or antibody tests, and tests for the management of COVID-19 patients. Within each category of tests, we review the commercialized testing platforms, their analyzing systems, specimen collection protocols, testing methodologies, supply chain logistics, and related attributes. Our discussion is essentially focused on test products that have been granted emergency use authorization by the FDA to detect and diagnose COVID-19 infections. Different strategies for scaled-up and faster screening are covered here, such as pooled testing, screening programs, and surveillance testing. The near-term challenges lie in detecting subtle infectivity profiles, mapping the transmission dynamics of new variants, lowering the cost for testing, training a large healthcare workforce, and providing test kits for the masses. Through this review, we try to understand the feasibility of universal access to COVID-19 testing and diagnostics in the near future while being cognizant of the implicit tradeoffs during the development and distribution cycles of new testing platforms.

The Effects of ILeVO and VOTiVO on Root Penetration and Behavior of the Soybean Cyst Nematode, Heterodera glycines.

The objective of this study was to determine the effects of ILeVO (fluopyram) and VOTiVO (Bacillus firmus I-1582) seed treatments on Heterodera glycines second-stage juvenile (J2) root penetration and behavior. In a growth chamber experiment, roots of soybeans grown from treated or untreated seeds were inoculated with H. glycines J2s at soil depths of 2.5, 5, or 7.5 cm. ILeVO significantly reduced H. glycines root penetration compared with the untreated control, but only when J2s were inoculated at a soil depth of 2.5 cm, which was near the seed. Changes in nematode behavior were assessed by collecting 60-s videos of J2s after 2 h of exposure to exudates from treated seeds or radicles from treated seeds or from soil leachates in which treated seeds were planted. X- and y-coordinates of each of the 13 reference points were recorded every hour for 24 h. A custom program analyzed and transformed the coordinates into nematode motion parameters (speed and total change in curvature). ILeVO, but not VOTiVO, seed exudates significantly reduced J2 speed relative to the untreated control. Soil leachates from ILeVO or VOTiVO treatments had no consistent effect on H. glycines speed or total change in curvature compared with the untreated control. In another experiment, treated or untreated seeds were incubated in wells of 6-well tissue culture plates containing 11.5% Pluronic gel. Seeds were removed after 2 h, and approximately 50 J2s then were pipetted into each well. The plates were scanned every 60 min for 24 h, and the number of J2s in each well that moved a minimum distance of ≥300 µm was determined using another custom software program. ILeVO, but not VOTiVO, significantly reduced the movement of J2 populations relative to control wells in which no seeds were added. And wells that had seeds, treated or not, yielded significantly less J2 movement compared with the no-seed control. The results of these experiments indicate that ILeVO reduces activity on H. glycines J2s but may not affect nematodes beyond a limited area surrounding the treated seed.

Movement and Motion of Soybean Cyst Nematode Heterodera glycines Populations and Individuals in Response to Abamectin.

Two new in vitro methods were developed to analyze plant-parasitic nematode behavior, at the population and the individual organism levels, through time-lapse image analysis. The first method employed a high-resolution flatbed scanner to monitor the movement of a population of nematodes over a 24-h period at 25°C. The second method tracked multiple motion parameters of individual nematodes on a microscopic scale, using a high-speed camera. Changes in movement and motion of second-stage juveniles (J2) of the soybean cyst nematode Heterodera glycines Ichinohe were measured after exposure to a serial dilution of abamectin (0.1 to 100 µg/ml). Movement and motion of H. glycines were significantly reduced as the concentration of abamectin increased. The effective range of abamectin to inhibit movement and motion of H. glycines J2 was between 1.0 and 10 µg/ml. Proof-of-concept experiments for both methods produced one of the first in vitro sensitivity studies of H. glycines to abamectin. The two methods developed allow for higher-throughput analysis of nematode movement and motion and provide objective and data-rich measurements that are difficult to achieve from conventional microscopic laboratory methods.

Avicta and Clariva Affect the Biology of the Soybean Cyst Nematode, Heterodera glycines.

Nematicidal seed treatments are a relatively new strategy for managing plant-parasitic nematodes in row crops. Two such seed treatments, Avicta (abamectin) and Clariva (Pasteuria nishizawae), are marketed by Syngenta for use against Heterodera glycines in soybean production in the upper Midwest. The specific effects of these seed treatments on the biology of the nematode have not been previously reported. The effects of Avicta and Clariva on H. glycines hatching, movement, attraction, penetration, development, and reproduction were determined in controlled-environment experiments. Avicta inhibited juvenile movement and penetration at the seed depth and 3 cm below the seed. Clariva inhibited juvenile movement and penetration 3 and 5 cm below the seed and nematode development within the roots of young plants. Both seed treatments affected nematodes in 10- and 20-day-old plants, but effects were not detected on nematodes developing in older plants (30 and 60 days) with larger root systems. These results provide details of the specific mechanisms of early-season protection provided by Avicta and Clariva seed treatments.

Assessment of toxicity and tolerability of a combination vehicle; 5% Pharmasolve, 45% Propylene glycol and 50% Polyethylene glycol 400 in rats following repeated intravenous administration.

The selection of a suitable vehicle for administration of NCEs in non-clinical studies is always a challenge for poorly soluble compounds. Challenge is increased if the dose formulation is intended for intravenous (i.v.) administration where isotonic, biologically compatible pH and solution form is an absolute requirement. Vehicle toxicity and tolerability data are not readily available for a number of combination vehicles therefore, an i.v. tolerability studies was planned in rats with 5% v/v Pharmasolve (NMP), 45% v/v Propylene glycol (PG) and 50% v/v Polyethylene glycol (PEG) 400 combination, at dose volume of 0.5, 1, 2 and 5 mL/kg body weight for 28 days. The vehicle combination was administered via lateral tail vein and effects on clinical signs, body weights, feed consumption, clinical pathology and histopathology were evaluated. Clinical signs of toxicity like tremors, convulsions and death were noticed at 5 mL/kg during the course of the study. At 2 mL/kg, injection site injury without systemic toxicity was noticed. In conclusion, 1 mL/kg of a combination vehicle of 5% NMP, 45% PG and 55% PEG 400 can be administered intravenously once-a-day up to 28 days without any discomfort or injury to rats.

Chip Technologies for Screening Chemical and Biological Agents Against Plant-Parasitic Nematodes.

Plant-parasitic nematodes cause substantial damage to agricultural crops worldwide. Long-term management of these pests requires novel strategies to reduce infection of host plants. Disruption of nematode chemotaxis to root systems has been proposed as a potential management approach, and novel assays are needed to test the chemotactic behavior of nematodes against a wide range of synthetic chemicals and root exudates. Two microfluidic chips were developed that measure the attraction or repulsion of nematodes to chemicals ("chemical chip") and young plant roots ("root chip"). The chip designs allowed for chemical concentration gradients to be maintained up to 24 h, the nematodes to remain physically separate from the chemical reservoirs, and for images of nematode populations to be captured using either a microscope or a flatbed scanner. In the experiments using the chemical chips, seven ionic solutions were tested on second-stage juveniles (J2s) of Meloidogyne incognita and Heterodera glycines. Results were consistent with previous reports of repellency of M. incognita to a majority of the ionic solutions, including NH4NO3, KNO3, KCl, MgCl2, and CaCl2. H. glycines was found to be attracted to both NH4NO3 and KNO3, which has not been reported previously. A software program was written to aid in monitoring the location of nematodes at regular time intervals using the root chip. In experiments with the root chip, H. glycines J2s were attracted to roots of 3-day-old, susceptible (cultivar Williams 82) soybean seedlings, and attraction of H. glycines to susceptible soybean was similar across the length of the root. Attraction to resistant (cultivar Jack) soybean seedlings relative to the water only control was inconsistent across runs, and H. glycines J2s were not preferentially attracted to the roots of resistant or susceptible cultivars when both were placed on opposite sides of the same root chip. The chips developed allow for direct tests of plant-parasitic nematode chemotaxis to chemicals and roots with minimal human intervention.

Guided-mode-resonance-enhanced measurement of thin-film absorption.

We present a numerical and experimental study of a guided-mode-resonance (GMR) device for detecting surface-bound light-absorbing thin films. The GMR device functions as an optical resonator at the wavelength strongly absorbed by the thin film. The GMR mode produces an evanescent field that results in enhanced optical absorption by the thin film. For a 100-nm-thick lossy thin film, the GMR device enhances its absorption coefficients over 26 × compared to a conventional glass substrate. Simulations show the clear quenching effect of the GMR when the extinction coefficient is greater than 0.01. At the resonant wavelength, the reflectance of the GMR surface correlates well with the degree of optical absorption. GMR devices are fabricated on a glass substrate using a surface-relief grating and a titanium-dioxide coating. To analyze a visible absorbing dye, the reflection coefficient of dye-coated GMR devices was measured. The GMR-based method was also applied to detecting acid gases, such as hydrochloric vapor, by monitoring the change in absorption in a thin film composed of a pH indicator, bromocresol green. This technique potentially allows absorption analysis in the visible and infrared ranges using inexpensive equipment.

Mutagenicity and clastogenicity evaluation of metaphenoxy benzyl chloride by ames and micronucleus assays.

Metaphenoxy Benzyl Chloride (3-PBC; CAS # 53874-66-1) is a commonly used intermediate in organic synthesis and is a widely used chemical building block. There is likelihood of human contact with 3-PBC in the process of organic or pesticide synthesis and even through as impurity in the product. Further, this chemical has been reported to be found in water reservoirs causing a threat to aqueous flaura and fauna. Genotoxic alert has been suspected for the chemical 3-PBC based on its structure hence, the impetus of present work was to assess the mutagenic potential of 3-PBC using Ames bacterial reverse-mutation assay and in vitro micronucleus assay. 3-PBC was tested for mutagenic potential at six different concentrations, with 0.05 (without metabolic activation) and 0.50 (with metabolic activation) µL/plate as the highest concentrations, followed by five lower concentrations with 2-fold spacing. In clastogenic evaluation, 3-PBC was tested at concentrations ranged from 0.31 to 4.88 µL/mL to assess micronucleus induction in mammalian cells viz. Chinese Hamster Ovarian-K1 cells (CHO-K1 cells). In the Ames assay, 3-PBC did not show mutagenicity in all five tester strains of Salmonella typhimurium viz. TA98, TA100, TA102, TA1535 and TA1537 both in the presence and absence of a metabolic activation system and found to be nonclastogenic when evaluated in "CHO-K1 cells".

An automated, high-resolution phenotypic assay for adult Brugia malayi and microfilaria.

Brugia malayi are thread-like parasitic worms and one of the etiological agents of Lymphatic filariasis (LF). Existing anthelmintic drugs to treat LF are effective in reducing the larval microfilaria (mf) counts in human bloodstream but are less effective on adult parasites. To test potential drug candidates, we report a multi-parameter phenotypic assay based on tracking the motility of adult B. malayi and mf in vitro. For adult B. malayi, motility is characterized by the centroid velocity, path curvature, angular velocity, eccentricity, extent, and Euler Number. These parameters are evaluated in experiments with three anthelmintic drugs. For B. malayi mf, motility is extracted from the evolving body skeleton to yield positional data and bending angles at 74 key point. We achieved high-fidelity tracking of complex worm postures (self-occlusions, omega turns, body bending, and reversals) while providing a visual representation of pose estimates and behavioral attributes in both space and time scales.

A rare case report of coexisting rheumatic heart disease and systemic lupus erythematous.

This case report discusses the rare coexistence of Systemic Lupus Erythematosus (SLE) and Rheumatic Heart Disease (RHD) in a 46-year-old female patient, challenging the conventional understanding of their distinct presentations. The patient exhibited migratory joint pains, palpitations, and shortness of breath. Diagnostic investigations confirmed SLE based on EULAR/ACR criteria, with positive anti-nuclear and anti-dsDNA antibodies. Concurrently, transthoracic echocardiography revealed severe mitral stenosis and regurgitation, leading to the diagnosis of RHD. The patient underwent successful open-heart surgery with mitral valve replacement. The discussion explores the rarity of this coexistence, emphasizing the need for cautious consideration and further research into potential immunological overlaps between SLE and RHD. The report concludes with a call for comprehensive studies to enhance our understanding of the pathophysiology connecting these two conditions.

Bioequivalence, food effect and comparative pharmacokinetics of SUVN-1105, a novel granule formulation of abiraterone acetate, to Zytiga in healthy male subjects.

PURPOSE: SUVN-1105 is a novel formulation of abiraterone acetate which was developed to demonstrate improved bioavailability, compared to Zytiga and Yonsa, and to reduce the dose and eliminate the food effect. A Phase 1 study was conducted to assess the bioequivalence, food effect, and comparative pharmacokinetics of SUVN-1105 to Zytiga in healthy male subjects. METHODS: The study comprised of 2 segments. Segment 1 was a single-center, 4-period crossover, open-label, fixed treatment sequence, single-dose study to evaluate the safety and pharmacokinetics of SUVN-1105 (N = 12 subjects per period). Segment 2 was a single-center, open-label, single-dose, randomized, 4-period, 4-treatment, 4-sequence crossover study to evaluate bioequivalence and comparative pharmacokinetics of SUVN-1105 against Zytiga (N = 44) under overnight fasted, modified fasted, and fed conditions. RESULTS: Abiraterone exposures appeared to increase proportionately with SUVN-1105 dose (200 mg vs. 250 mg) in Segment 1. In Segment 2, abiraterone exposures of 250 mg SUVN-1105 in the fasted or fed conditions were higher than those of Zytiga 1000 mg in the overnight fasted conditions. Abiraterone exposures of 250 mg SUVN-1105 decreased in the fed conditions (64% and 29% decrease in Cmax and AUC, respectively) compared to overnight fasted conditions. CONCLUSIONS: The abiraterone exposures of 250 mg SUVN-1105 in the fasted or fed conditions fall within the abiraterone exposures of 1000 mg Zytiga in fasted and modified fasted conditions. Single doses of SUVN-1105 were safe and well-tolerated in healthy males both in the fasted and fed conditions.

Variations in the plasticity of functional traits indicate the differential impacts of abiotic and biotic factors on the structure and growth of trees in tropical dry forest fragments.

Abiotic and biotic factors have considerable impact on the plasticity of plant functional traits, which influences forest structure and productivity; however, their inter-relationships have not been quantified for fragmented tropical dry forest (TDF) ecosystems. We asked the following questions: (1) what are the variations in the plasticity of functional traits due to soil moisture availability in TDF fragments? (2) what are the roles of soil nutrients and forest disturbances in influencing variations in the plasticity of functional traits in the TDF fragments? and (3) how do the variations in the plasticity of functional traits influence the structure and productivity of TDF fragments? Based on linear mixed-effects results, we observed significant variations among tree species for soil moisture content (SMC) under the canopy and selected functional traits across forest fragments. We categorized tree species across fragments by principal component analysis (PCA) and hierarchical clustering on principal components (HCPC) analyses into three functional types, viz., low wood density high deciduous (LWHD), high wood density medium deciduous (HWMD), and high wood density low deciduous (HWLD). Assemblage of functional traits suggested that the LWHD functional type exhibits a drought-avoiding strategy, whereas HWMD and HWLD adopt a drought-tolerant strategy. Our study showed that the variations in functional trait plasticity and the structural attributes of trees in the three functional types exhibit contrasting affinity with SMC, soil nutrients, and disturbances, although the LWHD functional type was comparatively more influenced by soil resources and disturbances compared to HWMD and HWLD along the declining SMC and edge distance gradients. Plasticity in functional traits for the LWHD functional type exhibited greater variations in traits associated with the conservation of water and resources, whereas for HWMD and HWLD, the traits exhibiting greater plasticity were linked with higher productivity and water transport. The cumulative influence of SMC, disturbances, and functional trait variations was also visible in the relative abundance of functional types in large and small sized fragments. Our analysis further revealed the critical differences in the responses of functional trait plasticity of the coexisting tree species in TDF, which suggests that important deciduous endemic species with drought-avoiding strategies might be prone to strategic exclusion under expected rises in anthropogenic disturbances, habitat fragmentation, and resource limitations.

Analytical modeling of the ion number fluctuations in biological ion channels.

Ion channels are transmembrane proteins that regulate and maintain the ionic concentrations across the cell membrane. Modeling the atomistic-level ionic flux through these channels is crucial for the understanding of several neurological diseases and related pharmaceutical discoveries. Experimental techniques now provide information about the channel's physical structure which helps in developing realisticion transport models. Ions entering a channel follow different trajectories as they traverse the channel; each associated with a certain probability. Quantities that explain these trajectories are the translocation and return probabilities, average lifetime, and spectral density (an experimentally accessible parameter) of ion number fluctuations. Theoretical analysis of ion transport has been limited to low-resolution continuum diffusion-based or kinetic-based models. Such analytical models fail to include key factors affecting the ionic conduction. In this paper, we extend previous models by an electro-diffusion model incorporating the effects of electric field, energy barrier, and rate-limited association/dissociation of ions with surface charges inside the channel. Survival probability and spectral density are derived from the analytical model.

Mutagenicity and clastogenicity evaluation of tacrine by Ames and micronucleus assays.

Tacrine was evaluated for its mutagenic and clastogenic activities using the Ames bacterial reverse-mutation assay and the rodent bone marrow micronucleus assay. Tacrine was tested for mutagenic potential at six different concentrations, with 1,250 µg/plate as the highest concentration, followed by five lower concentrations with 2-fold spacing. In clastogenic evaluation, tacrine was administered orally to Wistar rats for 2 days at 5, 10, and 20 mg/kg body weights to assess micronucleus induction in bone marrow erythrocytes. In the Ames assay, tacrine showed nonmutagenicity in four tester strains of Salmonella typhimurium viz. TA98, TA100, TA102, and TA1535, but it was found to be mutagenic in the TA1537 tester strain, both in the presence and absence of a metabolic activation system. Tacrine was found to be nonclastogenic on bone marrow cells of rats at all doses tested and was found to be mutagenic in only the TA1537 strain of Salmonella.

18F-FDG 18F-FDG Positron Emission Tomography Imaging of Cortical Reorganization in Spinal Trauma.

Objective: Spinal cord injury (SCI) extensively impacts the sensorimotor reorganization in the brain. The effects can be both anatomical and functional. To date, not many studies using 18F-Fluoro-2-Deoxyglucose positron emission tomography (18F-FDG PET) to evaluate metabolic changes in the brain are done. Understanding such changes is crucial for developing clinical management and evidence-based rehabilitation strategies for these patients. Subjects and Methods: In this study, we compared 18F-FDG PET imaging of 6 SCI patients with complete paraplegia and 19 controls. Statistical parametric mapping software was utilized to compare the images on a voxel to voxel basis (significance level P < 0.05 and clusters having >50 voxels). Results: The study showed raised metabolism in supplementary motor areas, comprehension centers, some areas in the parietal and temporal lobe, putamen and cerebellum while reduced metabolic uptake in areas like anterior cingulate gyrus, hippocampus and sensory cortical areas when SCI patients were compared against healthy controls. The frontal lobe showed varied results where certain regions showed higher metabolism while the others showed lower in patients compared with controls. Conclusion: Cerebral deafferentation or disuse atrophy can be linked with reduced metabolism while raised uptake can be associated with initiation and planning of movement and cognitive changes in the brain posttrauma.

Safety, Tolerability, and Pharmacokinetics of Ropanicant (SUVN-911), a Novel Alpha4 Beta2 Nicotinic Acetylcholine Receptor (α4ß2 nAChR) Antagonist, in Healthy Adult and Elderly Subjects.

BACKGROUND AND OBJECTIVES: Ropanicant hydrochloride (previously known as SUVN-911, hereinafter referred to as ropanicant) is a novel alpha4 beta2 nicotinic acetylcholine receptor (α4ß2 nAchR) antagonist being developed for the treatment of major depressive disorder. The objectives of the present studies were to evaluate the safety, tolerability, and pharmacokinetics of ropanicant after single and multiple ascending doses and to evaluate the effect of food, sex, and age on its pharmacokinetics in healthy subjects. METHODS: Two phase I studies have been conducted for ropanicant. Study 1 is a randomized, double-blind, placebo-controlled, first-in-human study to evaluate the safety, tolerability, and pharmacokinetics of single ascending doses (0.5, 6, 15, 30, and 60 mg) and multiple ascending doses (15, 30, and 45 mg) of ropanicant administered orally for 14 days to healthy male subjects. In Study 2, the effect of food, sex, and age on ropanicant pharmacokinetics was evaluated following a single 30-mg oral dose. RESULTS: Ropanicant at single doses up to 60 mg and multiple doses up to 45 mg once daily was found to be safe and well tolerated in healthy subjects. The most frequently reported adverse events were headache and nausea. Ropanicant exposures were more than dose proportional following single and multiple administrations. Urinary excretion of unchanged ropanicant was low across the doses. Upon multiple dosing, 1.5- to 2.5-fold higher exposures for maximum concentration and 1.6- to 4.0-fold higher exposures for area under the concentration-time curve from time 0-24 h were observed on day 14 as compared with day 1. Sex had an effect on the pharmacokinetics of ropanicant as a 64% higher area under the concentration-time curve from time 0 to 24 h and a 26% higher maximum concentration was observed in female adults when compared with male adults. Plasma exposures were comparable in fasted versus fed conditions and in adult versus elderly subjects. CONCLUSIONS: Ropanicant was found to be safe and well tolerated following single and multiple oral administrations in healthy subjects. Ropanicant showed nonlinear pharmacokinetics and accumulation following multiple dosing. Urinary excretion represents an insignificant elimination pathway for ropanicant. Ropanicant pharmacokinetics were sex dependent, and food and age had no effect on its pharmacokinetics. CLINICAL TRIAL REGISTRATION: NCT03155503 and NCT03551288.

Effect of Concurrent Use of Memantine on the Efficacy of Masupirdine (SUVN-502): A Post Hoc Analysis of a Phase 2 Randomized Placebo-Controlled Study.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration in cognition, memory and activities of daily living. Selective blockade of serotonin-6 (5-HT6) receptors, which are exclusively localized to the central nervous system, is reported to play an important role in learning and memory. Masupirdine is a potent and selective 5-HT6 receptor antagonist with pro-cognitive properties in animal models of cognition. METHODS: The efficacy and safety of masupirdine were evaluated in patients with moderate AD concurrently treated with donepezil and memantine. A total of 564 patients were randomized in a 1:1:1 ratio. The study consisted of a 26-week double-blind treatment period. The primary efficacy outcome was the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog 11). Changes from baseline were analyzed using a mixed effects model for repeated measures (MMRM). In exploratory post hoc analyses, patients were subdivided based on the use of memantine dosage forms and memantine plasma concentrations, to evaluate the impact of memantine on the efficacy of masupirdine. RESULTS: In an exploratory post hoc analysis, less worsening in cognition (ADAS-Cog 11 scores) was observed with masupirdine treatment as compared with placebo in patients whose trough memantine plasma concentrations were ≤ 100 ng/mL. CONCLUSIONS: Although prespecified study endpoints of the phase 2 study were not met, these exploratory post hoc subgroup observations are hypothesis-generating and suggest that the efficacy of masupirdine was adversely affected by concurrent therapy with memantine. Further assessment of masupirdine to determine its potential role as a treatment option for cognitive deficits associated with AD is warranted. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (NCT02580305).