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PloS One 2023Bangladesh has been ranked as one of the world's top countries affected by climate change, particularly in terms of agricultural crop sector. The purpose of this study...
Bangladesh has been ranked as one of the world's top countries affected by climate change, particularly in terms of agricultural crop sector. The purpose of this study is to identify spatial and temporal changes and trends in long-term climate at local and national scales, as well as their implications for rice yield. In this study, Modified Mann-Kendall and Sen's slope tests were used to detect significant trends and the magnitude of changes in temperature and rainfall. The temperature and rainfall data observed and recorded at 35 meteorological stations in Bangladesh over 65-years in the time span between the years 1949 and 2013 have been used to detect these changes and trends of variation. The results show that mean annual Tmean, Tmin, and Tmax have increased significantly by 0.13°C, 0.13°C, and 0.13°C/decade, respectively. The most significant increasing trend in seasonal temperatures for the respective Tmean, Tmin, and Tmax was 0.18°C per decade (post-monsoon), 0.18°C/decade (winter), and 0.23°C/decade (post-monsoon), respectively. Furthermore, the mean annual and pre-monsoon rainfall showed a significant increasing trend at a rate of 4.20 mm and 1.35 mm/year, respectively. This paper also evaluates climate variability impacts on three major rice crops, Aus, Aman, and Boro during 1970-2013. The results suggest that crop yield variability can be explained by climate variability during Aus, Aman, and Boro seasons by 33, 25, and 16%, respectively. Maximum temperature significantly affected the Aus and Aman crop yield, whereas rainfall significantly affected all rice crops' yield. This study sheds light on sustainable agriculture in the context of climate change, which all relevant authorities should investigate in order to examine climate-resilient, high-yield crop cultivation.
Topics: Temperature; Oryza; Climate Change; Bangladesh; Meteorology; Crops, Agricultural; Amantadine
PubMed: 37824463
DOI: 10.1371/journal.pone.0292668 -
The Journal of International Medical... Oct 2023Long-term use of antipsychotics or other dopamine antagonists can result in the extrapyramidal side effect of tardive dyskinesia (TD).Case presentation: An 18-year-old...
BACKGROUND
Long-term use of antipsychotics or other dopamine antagonists can result in the extrapyramidal side effect of tardive dyskinesia (TD).Case presentation: An 18-year-old female patient experienced abnormal speech and behavior and because of an equivocal diagnosis, she was given daily doses of 300 mg of quetiapine and 60 mg of ziprasidone. She had used these medications for 2 years before the appearance of involuntary abnormal movements. These movements, which were classified as TD, steadily worsened and markedly interfered with her daily life. Following a trial-and-error course of therapy with vitamin E, vitamin B6, amantadine, valproic acid sodium, lorazepam, and diazepam, the drugs were gradually reduced and stopped, yet the aberrant movements persisted. Finally, the patient was given olanzapine, clonazepam, baclofen, and gabapentin. The Abnormal Involuntary Movement Scale was used to assess changes in the patient's condition. Her TD was efficiently managed through co-administration of olanzapine, clonazepam, baclofen, and gabapentin.
CONCLUSIONS
The possibility of TD inducing by antipsychotic use is a clinical concern, even though atypical antipsychotics decrease the incidence of extrapyramidal side effects, and it cannot be entirely excluded. This report provides useful insights into the management of TD and will help clinicians manage similar cases.
Topics: Humans; Female; Adolescent; Olanzapine; Tardive Dyskinesia; Clonazepam; Gabapentin; Baclofen; Antipsychotic Agents
PubMed: 37812512
DOI: 10.1177/03000605231195154 -
Scientific Reports Oct 2023Metabolic profiling offers huge potential to highlight markers and mechanisms in support of toxicology and pathology investigations during drug development. The main...
Metabolic profiling offers huge potential to highlight markers and mechanisms in support of toxicology and pathology investigations during drug development. The main objective was to modify therapy with adamantane derivatives: amantadine and rimantadine, to increase their bioavailability and evaluate the influence of such therapy on drug metabolism using Saccharomyces cerevisiae as the model organism. In this study, the profile of endogenous metabolites of a model organism was measured and interpreted to provide an opportunity to investigate changes induced by treatment with amantadine and rimantadine. It was found that resveratrol supplementation synergistically enhanced the effects of amantadine treatment and increased rimantadine metabolism, potentially reducing side effects. The fingerprinting strategy was used as an efficient technique for qualitatively evaluating and monitoring changes in the profiles of endogenous components and their contents in a model organism. Chemometric tools were employed to find marker compounds that can be defined as characteristic indicators of a pharmacological response to a therapeutic intervention. An improved understanding of the mechanisms involved in drug effect and an increased ability to predict individual variations in the drug response of organisms will improve the treatment process and the development of new therapies.
Topics: Rimantadine; Adamantane; Secondary Metabolism; Amantadine; Metabolic Clearance Rate
PubMed: 37798340
DOI: 10.1038/s41598-023-43540-w -
Research Square Sep 2023Prediction of high-risk events in mental disorder patients is crucial. In our previous study, we developed a deep learning model: DeepBiomarker by using electronic...
Prediction of Adverse Events Risk in Patients with Comorbid Post- Traumatic Stress Disorder and Alcohol Use Disorder Using Electronic Medical Records by Deep Learning Models.
BACKGROUND
Prediction of high-risk events in mental disorder patients is crucial. In our previous study, we developed a deep learning model: DeepBiomarker by using electronic medical records (EMR) to predict suicide related event (SRE) risk in post-traumatic stress disorder (PTSD) patients.
METHODS
We applied DeepBiomarker2 through data integration of multimodal information: lab test, medication, co-morbidities, and social determinants of health. We analyzed EMRs of 5,565 patients from University of Pittsburgh Medical Center with a diagnosis of PTSD and alcohol use disorder (AUD) on risk of developing an adverse event (opioid use disorder, SREs, depression and death).
RESULTS
DeepBiomarker2 predicted whether a PTSD + AUD patient will have a diagnosis of any adverse events (SREs, opioid use disorder, depression, death) within 3 months with area under the receiver operator curve (AUROC) of 0.94. We found piroxicam, vilazodone, dronabinol, tenofovir, suvorexant, empagliflozin, famciclovir, veramyst, amantadine, sulfasalazine, and lamivudine to have potential to reduce risk.
CONCLUSIONS
DeepBiomarker2 can predict multiple adverse event risk with high accuracy and identify potential risk and beneficial factors. Our results offer suggestions for personalized interventions in a variety of clinical and diverse populations.
PubMed: 37790550
DOI: 10.21203/rs.3.rs-3299369/v1 -
Amantadine-Induced Craniofacial Myoclonus: Distinctive Iatrogenic Dysarthria in Parkinson's Disease.Movement Disorders Clinical Practice Sep 2023Amantadine is a widely prescribed medication in Parkinson's disease (PD). A distinctive craniofacial distribution of myoclonus with speech impairment is an... (Review)
Review
BACKGROUND
Amantadine is a widely prescribed medication in Parkinson's disease (PD). A distinctive craniofacial distribution of myoclonus with speech impairment is an underrecognized iatrogenic complication in amantadine-treated patients with PD.
CASES
We report 7 patients with idiopathic PD (disease duration, 6-21 years) who developed speech-induced craniofacial-predominant myoclonus with "stuttering-like" dysarthria and speech arrests days to months after amantadine initiation or dose increase. Renal insufficiency was identified as a risk factor in 4 cases. In all cases, reduction or discontinuation of amantadine markedly attenuated the myoclonus and restored speech intelligibility.
LITERATURE REVIEW
Amantadine can induce subcortical segmental or generalized myoclonus. A report in 1996 of "vocal myoclonus" in an amantadine-treated patient with PD was the first observation of a focal distribution of myoclonus, particularly affecting speech. Since then, few cases of craniofacial myoclonus with speech impairment have been reported, none with accompanying video. With 1 exception, the craniofacial distribution was part of a generalized pattern of amantadine-induced myoclonus. Comorbid renal insufficiency is a recognized risk factor.
CONCLUSIONS
Speech-induced craniofacial myoclonus, with marked "stuttering-like" dysarthria and speech arrests, is a disabling iatrogenic complication in PD that resolves upon amantadine discontinuation.
PubMed: 37772280
DOI: 10.1002/mdc3.13828 -
International Journal of Molecular... Sep 2023In an ever-increasing aged world, Alzheimer's disease (AD) represents the first cause of dementia and one of the first chronic diseases in elderly people. With 55... (Review)
Review
In an ever-increasing aged world, Alzheimer's disease (AD) represents the first cause of dementia and one of the first chronic diseases in elderly people. With 55 million people affected, the WHO considers AD to be a disease with public priority. Unfortunately, there are no final cures for this pathology. Treatment strategies are aimed to mitigate symptoms, i.e., acetylcholinesterase inhibitors (AChEI) and the N-Methyl-D-aspartate (NMDA) antagonist Memantine. At present, the best approaches for managing the disease seem to combine pharmacological and non-pharmacological therapies to stimulate cognitive reserve. Over the last twenty years, a number of drugs have been discovered acting on the well-established biological hallmarks of AD, deposition of β-amyloid aggregates and accumulation of hyperphosphorylated tau protein in cells. Although previous efforts disappointed expectations, a new era in treating AD has been working its way recently. The Food and Drug Administration (FDA) gave conditional approval of the first disease-modifying therapy (DMT) for the treatment of AD, aducanumab, a monoclonal antibody (mAb) designed against Aβ plaques and oligomers in 2021, and in January 2023, the FDA granted accelerated approval for a second monoclonal antibody, Lecanemab. This review describes ongoing clinical trials with DMTs and non-pharmacological therapies. We will also present a future scenario based on new biomarkers that can detect AD in preclinical or prodromal stages, identify people at risk of developing AD, and allow an early and curative treatment.
Topics: United States; Humans; Aged; Alzheimer Disease; Acetylcholinesterase; Amyloid beta-Peptides; Memantine; Antibodies, Monoclonal
PubMed: 37762203
DOI: 10.3390/ijms241813900 -
European Journal of Pharmaceutical... Dec 2023Intrinsic membrane permeability is one of several factors that critically determine the intestinal absorption of a chemical. The intrinsic membrane permeability of a...
Intrinsic membrane permeability is one of several factors that critically determine the intestinal absorption of a chemical. The intrinsic membrane permeability of a chemical is usually extracted from transwell experiments with Caco-2 or MDCK cells, preferably by the pK-Flux method, which is considered the method of choice when aqueous boundary layer effects need to be excluded. The pK-Flux method has two variants, the iso-pH method, where apical and basolateral pH are equal, and the gradient-pH method, where apical and basolateral pH are different. The most commonly used method is the gradient-pH method, as it is intended to reflect the pH-conditions in the gastrointestinal tract. However, concentration-shift effects caused by the applied pH-difference between apical and basolateral compartment in the gradient-pH method have not been considered in the evaluation of the experimental data in the past. Consequently, incorrect intrinsic membrane permeabilities have been determined. In this work, we present a revised method for extracting the intrinsic membrane permeability from gradient-pH data that considers concentration-shift effects in the basolateral aqueous boundary layer and filter as well as in the cytosol. Furthermore, we propose the use of the iso-pH method, where only concentration-shift effects in the cytosol need to be considered, as an alternative to the gradient-pH method. We use the five lipophilic bases amantadine, chloroquine, propranolol, venlafaxine and verapamil as examples to compare gradient-pH method and iso-pH method with regard to the extractability of the intrinsic membrane permeability. For lipophilic bases, the iso-pH method proves to be advantageous. All intrinsic membrane permeabilities determined in this work were substantially higher than the intrinsic membrane permeabilities reported in literature.
Topics: Humans; Caco-2 Cells; Cell Membrane Permeability; Propranolol; Intestinal Absorption; Permeability; Hydrogen-Ion Concentration
PubMed: 37751809
DOI: 10.1016/j.ejps.2023.106592 -
Archives of Rehabilitation Research and... Sep 2023Symptoms after mild traumatic brain injury (MTBI) can persist for greater than 1 month in up to 20% of individuals, yet there are no current medications approved by the...
Symptoms after mild traumatic brain injury (MTBI) can persist for greater than 1 month in up to 20% of individuals, yet there are no current medications approved by the Food and Drug Administration for treatment of specific concussion related sequelae. Amantadine, a dopamine agonist and N-Methyl-D-aspartate antagonist, is increasingly being used as a treatment option for individuals with traumatic brain injury across the spectrum of injury severity. This case report describes a 22-year-old individual who sustained an MTBI without loss of consciousness or post-traumatic amnesia after striking their head against a metal cabinet. The individual was referred to an interdisciplinary outpatient brain rehabilitation program secondary to persistent symptoms after MTBI, was prescribed amantadine for post-traumatic headache 97 days after injury, and subsequently developed symptoms of serotonin syndrome (SS) within 10 days of medication initiation. While SS caused by amantadine has been described in individuals with renal failure, this case report is the first to describe amantadine precipitating SS - confirmed by a validated diagnostic criterion and successfully treated with lorazepam and cyproheptadine - in a patient with normal renal function already on duloxetine, bupropion, and gabapentin. This case report is important in elucidating potential contributions of amantadine to the development of SS and highlighting the important role clinicians have in assessing for polypharmacy when prescribing amantadine for individuals with traumatic and acquired brain injuries.
PubMed: 37744194
DOI: 10.1016/j.arrct.2023.100283 -
Epilepsia Dec 2023N-methyl-d-aspartate (NMDA) receptors are expressed at synaptic sites, where they mediate fast excitatory neurotransmission. NMDA receptors are critical to brain...
OBJECTIVE
N-methyl-d-aspartate (NMDA) receptors are expressed at synaptic sites, where they mediate fast excitatory neurotransmission. NMDA receptors are critical to brain development and cognitive function. Natural variants to the GRIN1 gene, which encodes the obligatory GluN1 subunit of the NMDA receptor, are associated with severe neurological disorders that include epilepsy, intellectual disability, and developmental delay. Here, we investigated the pathogenicity of three missense variants to the GRIN1 gene, p. Ile148Val (GluN1-3b[I481V]), p.Ala666Ser (GluN1-3b[A666S]), and p.Tyr668His (GluN1-3b[Y668H]).
METHODS
Wild-type and variant-containing NMDA receptors were expressed in HEK293 cells and primary hippocampal neurons. Patch-clamp electrophysiology and pharmacology were used to profile the functional properties of the receptors. Receptor surface expression was evaluated using fluorescently tagged receptors and microscopy.
RESULTS
Our data demonstrate that the GluN1(I481V) variant is inhibited by the open pore blockers ketamine and memantine with reduce potency but otherwise has little effect on receptor function. By contrast, the other two variants exhibit gain-of-function molecular phenotypes. Glycine sensitivity was enhanced in receptors containing the GluN1(A666S) variant and the potency of pore block by memantine and ketamine was reduced, whereas that for MK-801 was increased. The most pronounced functional deficits, however, were found in receptors containing the GluN1(Y668H) variant. GluN1(Y668H)/2A receptors showed impaired surface expression, were more sensitive to glycine and glutamate by an order of magnitude, and exhibited impaired block by extracellular magnesium ions, memantine, ketamine, and MK-801. These variant receptors were also activated by either glutamate or glycine alone. Single-receptor recordings revealed that this receptor variant opened to several conductance levels and activated more frequently than wild-type GluN1/2A receptors.
SIGNIFICANCE
Our study reveals a critical functional locus of the receptor (GluN1[Y668]) that couples receptor gating to ion channel conductance, which when mutated may be associated with neurological disorder.
Topics: Humans; Memantine; Dizocilpine Maleate; Receptors, N-Methyl-D-Aspartate; Ketamine; HEK293 Cells; Glutamates; Neurodevelopmental Disorders; Glycine; Nerve Tissue Proteins
PubMed: 37734923
DOI: 10.1111/epi.17776 -
European Journal of Medicinal Chemistry Dec 2023Neurodegenerative processes characterizing Alzheimer's disease (AD) are strictly related to the impairment of cholinergic and glutamatergic neurotransmitter systems...
Neurodegenerative processes characterizing Alzheimer's disease (AD) are strictly related to the impairment of cholinergic and glutamatergic neurotransmitter systems which provoke synaptic loss. These experimental evidences still represent the foundation of the actual standard-of-care treatment for AD, albeit palliative, consisting on the coadministration of an acetylcholinesterase inhibitor and the NMDAR antagonist memantine. In looking for more effective treatments, we previously developed a series of galantamine-memantine hybrids where compound 1 (ARN14140) emerged with the best-balanced action toward the targets of interest paired to neuroprotective efficacy in a murine AD model. Unfortunately, it showed a suboptimal pharmacokinetic profile, which required intracerebroventricular administration for in vivo studies. In this work we designed and synthesized new hybrids with fewer rotatable bonds, which is related to higher brain exposure. Particularly, compound 2, bearing a double bond in the tether, ameliorated the biological profile of compound 1 in invitro studies, increasing cholinesterases inhibitory potencies and selective antagonism toward excitotoxic-related GluN1/2B NMDAR over beneficial GluN1/2A NMDAR. Furthermore, it showed increased plasma stability and comparable microsomal stability in vitro, paired with lower half-life and faster clearance in vivo. Remarkably, pharmacokinetic evaluations of compound 2 showed a promising increase in brain uptake in comparison to compound 1, representing the starting point for further chemical optimizations.
Topics: Humans; Mice; Animals; Galantamine; Memantine; Alzheimer Disease; Acetylcholinesterase; Cholinesterase Inhibitors; Receptors, N-Methyl-D-Aspartate
PubMed: 37734258
DOI: 10.1016/j.ejmech.2023.115803