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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 -
Annals of Palliative Medicine Nov 2023Improvements in radiation delivery and systemic therapies have resulted in few remaining indications for palliative whole brain radiation therapy (WBRT). Most centers...
BACKGROUND
Improvements in radiation delivery and systemic therapies have resulted in few remaining indications for palliative whole brain radiation therapy (WBRT). Most centers preferentially use stereotactic radiotherapy (SRT) and reserve WBRT for those with >15 lesions, leptomeningeal presentation, rapidly progressive disease, or limited estimated survival. Despite regional differences among preferred dose, fractionation, and treatment technique, we predict survival post-WBRT will remain poor-indicating appropriate application of WBRT in this era of SRT and improved systemic therapies.
METHODS
A multi-center, international retrospective analysis of patients receiving WBRT in 2022 was performed. Primary end point was survival after WBRT. De-identified data were analyzed centrally. Patients receiving WBRT as part of a curative regimen, prophylactically, or as bridging therapy were excluded. The collected data consisted of patient parameters including prescription dose and fractionation, use of neurocognitive sparing techniques and survival after WBRT. Survival was calculated via the Kaplan-Meier method.
RESULTS
Of 29,943 international RT prescriptions written at ten participating centers in 2022, 462 (1.5%) were for palliative WBRT. Participating centers were in the United States (n=138), the United Kingdom (n=111), Hong Kong (n=72), Italy (n=49), Belgium (n=45), Germany (n=27), Ghana (n=15), and Cyprus (n=5). Twenty-six different dose regimens were used. The most common prescriptions were for 3,000 cGy over 10 fractions (45.0%) and 2,000 cGy over 5 fractions (43.5%) with significant regional preferences (P<0.001). Prior SRT was delivered in 32 patients (6.7%), hippocampal avoidance (HA) was used in 44 patients (9.5%), and memantine was prescribed in 93 patients (20.1%). Survival ranged from 0 days to still surviving at 402 days post-treatment. The global median overall survival (OS) was 84 days after WBRT [95% confidence interval (CI): 68.0-104.0]. Actuarial survival at 7 days, 1 month, 3 months, and 6 months were 95%, 78%, 48%, and 32%, respectively. Twenty-seven patients (5.8%) were unable to complete their prescribed WBRT.
CONCLUSIONS
This moment-in-time analysis confirms that patients with poor expected survival are being appropriately selected for WBRT-illustrating the dwindling indications for WBRT-and demonstrates the variance in global practice. Since poor survival precludes patients from deriving benefit, memantine and HA are best suited in carefully selected cases.
Topics: Humans; Brain Neoplasms; Retrospective Studies; Memantine; Cranial Irradiation; Radiosurgery; Brain
PubMed: 37731303
DOI: 10.21037/apm-23-448 -
Frontiers in Psychiatry 2023Antipsychotic-induced catatonia is an iatrogenic and debilitating adverse reaction, but there is a dearth of recent documented cases. This report describes a 35-year-old...
Antipsychotic-induced catatonia is an iatrogenic and debilitating adverse reaction, but there is a dearth of recent documented cases. This report describes a 35-year-old incarcerated Korean-American male with a history of unspecified psychosis who presented for antipsychotic induced catatonia after administration of haloperidol decanoate intramuscular (200 mg across the span of 1 week). Neurologic workup was performed including MRI, lumbar puncture, and electroencephalography. Despite an approximate month long hospitalization, benzodiazepine challenge, benztropine trial, and amantadine adjunct, our patient continued to experience bradykinesia, waxy flexibility, and mask-like facies, and was minimally verbally responsive. Several challenges in the treatment of incarcerated individuals at the hospital are highlighted in this case report, including adverse reaction to medication, difficulty of care coordination, and limited access to health records among providers.
PubMed: 37720901
DOI: 10.3389/fpsyt.2023.1092253