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

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

Atomic-layer deposited thulium oxide as a passivation layer on germanium

A comprehensive study of atomic-layer deposited thulium oxide (Tm2O3) on germanium has been conducted using x-ray photoelectron spectroscopy (XPS), vacuum ultra-violet variable angle spectroscopic ellipsometry, high-resolution transmission electron microscopy (HRTEM), and electron energy-loss spectroscopy. The valence band offset is found to be 3.05 ± 0.2 eV for Tm2O3/p-Ge from the Tm 4d centroid and Ge 3p3/2 charge-corrected XPS core-level spectra taken at different sputtering times of a single bulk thulium oxide sample. A negligible downward band bending of ∼0.12 eV is observed during progressive differential charging of Tm 4d peaks. The optical band gap is estimated from the absorption edge and found to be 5.77 eV with an apparent Urbach tail signifying band gap tailing at ∼5.3 eV. The latter has been correlated to HRTEM and electron diffraction results corroborating the polycrystalline nature of the Tm2O3 films. The Tm2O3/Ge interface is found to be rather atomically abrupt with sub-nanometer thickness. In addition, the band line-up of reference GeO2/n-Ge stacks obtained by thermal oxidation has been discussed and derived. The observed low reactivity of thulium oxide on germanium as well as the high effective barriers for holes (∼3 eV) and electrons (∼2 eV) identify Tm2O3 as a strong contender for interfacial layer engineering in future generations of scaled high-κ gate stacks on Ge

Efficacy and safety of empagliflozin in type 2 diabetes mellitus Saudi patients as add-on to antidiabetic therapy: a prospective, open-label, observational study

The Saudi Food and Drug Authority (SFDA) approved sodium-glucose cotransporter-2 (SGLT2) inhibitors in 2018. The efficacy and safety of empagliflozin (EMPA) have been confirmed in the U.S., Europe, and Japan for patients with type 2 diabetes mellitus (T2DM); however, analogous evidence is lacking for Saudi T2DM patients. Therefore, the current study aimed to assess the efficacy and safety of EMPA in Saudi patients (n = 256) with T2DM. This is a 12-week prospective, open-label, observational study. Adult Saudi patients with T2DM who had not been treated with EMPA before enrolment were eligible. The exclusion criteria included T2DM patients less than 18 years of age, adults with type one diabetes, pregnant women, paediatric population. The results related to efficacy included a significant decrease in haemoglobin A1c (HbA1c) (adjusted mean difference −0.93% [95% confidence interval (CI) −0.32, −1.54]), significant improvements in fasting plasma glucose (FPG) (−2.28 mmol/L [95% CI −2.81, −1.75]), and a reduction in body weight (−0.874 kg [95% CI −4.36, −6.10]) following the administration of 25 mg of EMPA once daily as an add-on to ongoing antidiabetic therapy after 12 weeks. The primary safety endpoints were the change in the mean blood pressure (BP) values, which indicated significantly reduced systolic and diastolic BP (−3.85 mmHg [95% CI −6.81, −0.88] and −0.06 mmHg [95% CI −0.81, −0.88], respectively) and pulse rate (−1.18 [95% CI −0.79, −3.15]). In addition, kidney function was improved, with a significant reduction in the urine albumin/creatinine ratio (UACR) (−1.76 mg/g [95% CI −1.07, −34.25]) and a significant increase in the estimated glomerular filtration rate (eGFR) (3.54 mL/min/1.73 m2 [95% CI 2.78, 9.87]). Furthermore, EMPA reduced aminotransferases (ALT) in a pattern (reduction in ALT > AST). The adjusted mean difference in the change in ALT was −2.36 U/L [95% CI −1.031, −3.69], while it was −1.26 U/L [95% CI −0.3811, −2.357] for AST and −1.98 U/L [95% CI −0.44, −3.49] for GGT. Moreover, in the EMPA group, serum high-density lipoprotein (HDL) significantly increased (0.29 mmol/L [95% CI 0.74, 0.15]), whereas a nonsignificant increase was seen in low-density lipoprotein (LDL) (0.01 mmol/L [95% CI 0.19, 0.18]) along with a significant reduction in plasma triglyceride (TG) levels (−0.43 mmol/L [95% CI −0.31, −1.17]). Empagliflozin once daily is an efficacious and tolerable strategy for treating Saudi patients with insufficiently controlled T2DM as an add-on to ongoing antidiabetic therapy

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks