Development of memantine as a drug for Alzheimer’s disease: A review of preclinical and clinical studies

Excitotoxicity contributes to neuronal cell death due to overstimulation of N-methyl-D-aspartate (NMDA) receptors by glutamate, which plays a significant role in the development and progression of Alzheimer’s disease (AD) and other neurodegenerative disorders. Studies have been conducted to identify a well-tolerated and selective NMDA receptor blocker in an effort to alleviate neurodegeneration. Memantine has been found to induce a distinct low-affinity NMDA receptor blockade in both preclinical and clinical studies Therefore, FDA approved this drug as a well-tolerated noncompetitive NMDA receptor blocker for treating moderate to severe cases of AD. Further, memantine showed neuroprotective effects in preclinical studies by selectively blocking excessive NMDA receptor activation. Altogether, this novel drug is well-tolerated and effective for treating moderate to severe AD in various clinical studies. This paper is a review of preclinical and clinical studies on the drug development process of memantine. Keywords: Memantine, Excitotoxicity, N-methyl-D-aspartate, Glutamate, Alzheimer’s disease, neurodegeneratio

An edge moving load on an orthotropic plate resting on a Winkler foundation

Steady-state motion of a bending moment along the edge of a semi-infinite orthotropic Kirchhoff plate supported by a Winkler foundation is considered. The analysis of the dispersion relation reveals a local minimum of the phase velocity, coinciding with the value of the group velocity, corresponding to the critical speed of the moving load. In contrast to a free plate, the bending edge wave on an elastically supported plate possesses a cut-off frequency, arising due to the stiffening effect of the foundation. It is shown that the steady-state solution of a moving load problem corresponds to a beam-like edge behaviour. This feature is then confirmed from the specialised parabolic-elliptic formulation, which is oriented to extracting the contribution of the bending edge wave to the overall dynamic response

Measures of neck muscle strength and their measurement properties in adults with chronic neck pain-a systematic review.

Measurement of neck muscle strength is common during the assessment of people with chronic neck pain (CNP). This systematic review evaluates the measurement properties (reliability, validity, and responsiveness) of neck muscle strength measures in people with CNP. This systematic review followed a PROSPERO registered protocol (CRD42021233290). Electronic databases MEDLINE (OVID interface), CINAHL, SPORTDiscuss via (EBSCO interface), EMBASE (OVID interface), and Web of Science were searched from inception to 21 June 2021. Screening, data extraction, and quality assessment (Consensus-based Standards for the selection of Health Measurement Instruments (COSMIN) checklist) were conducted independently by two reviewers. The overall strength of evidence was evaluated using the modified Grading of Recommendations Assessment, Development and Evaluation. From 794 records, nine articles were included in this review which concerned six different neck strength outcome measures. All studies evaluated reliability and one evaluated construct validity. The reliability of neck strength measures ranged from good to excellent. However, the risk of bias was rated as doubtful/inadequate for all except one study and the overall certainty of evidence was rated low/very low for all measures except for the measurement error of a handheld dynamometer. A multitude of measures are used to evaluate neck muscle strength in people with CNP, but their measurement properties have not been fully established. Further methodologically rigorous research is required to increase the overall quality of evidence. [Abstract copyright: © 2023. The Author(s).

Edge bending waves on an orthotropic elastic plate resting on the Winkler-Fuss foundation

The propagation of bending edge waves on an orthotropic plate supported by the Winkler-Fuss foundation subject to free edge boundary conditions is investigated. A dispersion relation is derived, with the analysis revealing a cut-off frequency and a local minimum of the phase velocity. The conventional sinusoidal profile of the eigensolution is then extended to a more general form, with the deflection expressed in terms of a single plane harmonic function

Hafnia and alumina on sulphur passivated germanium

In this work hafnia (HfO2) and alumina (Al2O3) films were deposited on germanium, using either water or oxygen plasma as the oxidant, by atomic layer deposition at 250 °C with and without sulphur passivation of the substrate. X-ray photoelectron spectroscopy was carried out to investigate the interface between both HfO2 and Al2O3 films and germanium. The results show that for hafnia and alumina deposited with water on pre-sulphur treated germanium there is negligible GeOx formation when compared to films grown using oxygen plasma. The results support the case for sulphur passivation of the interface

Effects of MS-153 on chronic ethanol consumption and GLT1 modulation of glutamate levels in male alcohol-preferring rats

We have recently shown that upregulation of glutamate transporter 1 (GLT1) in the brain is associated in part with reduction in ethanol intake in alcohol-preferring (P) male rats. In this study, we investigated the effects of a synthetic compound, (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), known to activate GLT1 on ethanol consumption as well as GLT1 expression and certain signaling pathways in P rats. P rats were given 24-hour concurrent access to 15% and 30% ethanol, water and food for five weeks. On week 6, P rats received MS-153 at a dose of 50 mg/kg (i.p.) or a vehicle (i.p.) for five consecutive days. We also tested the effect of MS-153 on daily sucrose (10%) intake. Our studies revealed a significant decrease in ethanol intake at the dose of 50 mg/kg MS-153 from Day 1 through Day 14. In addition, MS-153 at dose of 50 mg/kg did not induce any significant effect on sucrose intake. Importantly, we found that MS-153 upregulated the GLT1 level in the nucleus accumbens (NAc) but not in the prefrontal cortex (PFC). In accordance, we found upregulation of nuclear NFkB-65 level in NAc in MS-153-treated group, however, IkB was downregulated in MS-153-treated group in NAc. We did not find any changes in NFkB-65 and IkB levels in PFC. Interestingly, we revealed that p-Akt was downregulated in ethanol vehicle treated groups in the NAc; this downregulation was reversed by MS-153 treatment. We did not observe any significant differences in glutamate aspartate transporter (GLAST) expression among all groups. These findings reveal MS-153 as a GLT1 modulator that may have potential as a therapeutic drug for the treatment of alcohol dependence

Impact of an Advanced Practice Pharmacist Type 2 Diabetes Management Program: A Pilot Study

Background: The purpose of this study was to describe the impact of an Advanced Practice Pharmacist (APh) on lowering hemoglobin A1c (HbA1c) in patients with type 2 diabetes within a patient centered medical home (PCMH) and to classify the types of therapeutic decisions made by the APh. Methods: This was a retrospective study using data from electronic health records. The study evaluated a partnership between Chapman University School of Pharmacy and Providence St. Joseph Heritage Healthcare that provided diabetes management by an Advanced Practice Pharmacist in a PCMH under a collaborative practice agreement. Change in the HbA1c was the primary endpoint assessed in this study. The type of therapeutic decisions made by the APh were also evaluated. Descriptive analysis and Wilcoxon signed rank test were used to analyze data. Results: The study included 35 patients with diagnosis of type 2 diabetes mellitus managed by an APh from May 2017 to December 2017. Most of the patients were 60-79 years old (68.5%), 45.7% were female, and 45.7% were of Hispanic/Latino ethnicity. The average HbA1c was 8.8%±1.4% (range=6.0%-12.4%) and 7.5%±1.4% (range=5.5%-12.4%) at the initial and final APh visit, respectively (p\u3c0.0001). Therapeutic decisions made by the APh included drug dose increase (35.5% of visits), drug added (16.4%), drug dose decrease (6.4%), drug switch (5.5%), and drug discontinuation (1.8%). Conclusion: The Advanced Practice Pharmacist’s interventions had a significant positive impact on lowering HbA1c in patients with type 2 diabetes mellitus in a PCMH. The most common therapeutic decisions made by the APh included drug dose increase and adding a new drug

Ge interface engineering using ultra-thin La2O3 and Y2O3 films: A study into the effect of deposition temperature

A study into the optimal deposition temperature for ultra-thin La2O3/Ge and Y2O3/Ge gate stacks has been conducted in this paper with the aim to tailor the interfacial layer for effective passivation of the Ge interface. A detailed comparison between the two lanthanide oxides (La2O3 and Y2O3) in terms of band line-up, interfacial features, and reactivity to Ge using medium energy ion scattering, vacuum ultra-violet variable angle spectroscopic ellipsometry (VUV-VASE), X-ray photoelectron spectroscopy, and X-ray diffraction is shown. La2O3 has been found to be more reactive to Ge than Y2O3, forming LaGeOx and a Ge sub-oxide at the interface for all deposition temperature studied, in the range from 44 °C to 400 °C. In contrast, Y2O3/Ge deposited at 400 °C allows for an ultra-thin GeO2 layer at the interface, which can be eliminated during annealing at temperatures higher than 525 °C leaving a pristine YGeOx/Ge interface. The Y2O3/Ge gate stack deposited at lower temperature shows a sub-band gap absorption feature fitted to an Urbach tail of energy 1.1 eV. The latter correlates to a sub-stoichiometric germanium oxide layer at the interface. The optical band gap for the Y2O3/Ge stacks has been estimated to be 5.7 ± 0.1 eV from Tauc-Lorentz modelling of VUV-VASE experimental data. For the optimal deposition temperature (400 °C), the Y2O3/Ge stack exhibits a higher conduction band offset (>2.3 eV) than the La2O3/Ge (∼2 eV), has a larger band gap (by about 0.3 eV), a germanium sub-oxide free interface, and leakage current (∼10−7 A/cm2 at 1 V) five orders of magnitude lower than the respective La2O3/Ge stack. Our study strongly points to the superiority of the Y2O3/Ge system for germanium interface engineering to achieve high performance Ge Complementary Metal Oxide Semiconductor technology

Alcohol Consumption Impairs the Ependymal Cilia Motility in the Brain Ventricles

Ependymal cilia protrude into the central canal of the brain ventricles and spinal cord to circulate the cerebral spinal fluid (CSF). Ependymal cilia dysfunction can hinder the movement of CSF leading to an abnormal accumulation of CSF within the brain known as hydrocephalus. Although the etiology of hydrocephalus was studied before, the effects of ethanol ingestion on ependymal cilia function have not been investigated in vivo. Here, we report three distinct types of ependymal cilia, type-I, type-II and type-III classified based upon their beating frequency, their beating angle, and their distinct localization within the mouse brain-lateral ventricle. Our studies show for the first time that oral gavage of ethanol decreased the beating frequency of all three types of ependymal cilia in both the third and the lateral rat brain ventricles in vivo. Furthermore, we show for the first time that hydin, a hydrocephalus-inducing gene product whose mutation impairs ciliary motility, and polycystin-2, whose ablation is associated with hydrocephalus are colocalized to the ependymal cilia. Thus, our studies reinforce the presence of three types of ependymal cilia in the brain ventricles and demonstrate the involvement of ethanol as a risk factor for the impairment of ependymal cilia motility in the brain

Interface Engineering Routes for a Future CMOS Ge-based Technology

We present an overview study of two germanium interface engineering routes, firstly a germanate formation via La2O3 and Y2O3, and secondly a barrier layer approach using Al2O3 and Tm2O3. The interfacial composition, uniformity, thickness, band gap, crystallinity, absorption features and valence band offset are determined using X-ray photoelectron spectroscopy, ultra violet variable angle spectroscopic ellipsometry, and high resolution transmission electron microscopy. The correlation of these results with electrical characterization data make a case for Ge interface engineering with rare-earth inclusion as a viable route to achieve high performance Ge CMOS.</jats:p