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Pharmaceuticals (Basel, Switzerland) Jun 2024Memory is one of the most important abilities of our brain. The process of memory and learning is necessary for the proper existence of humans in the surrounding...
The Influence of an Acute Administration of Cannabidiol or Rivastigmine, Alone and in Combination, on Scopolamine-Provoked Memory Impairment in the Passive Avoidance Test in Mice.
Memory is one of the most important abilities of our brain. The process of memory and learning is necessary for the proper existence of humans in the surrounding environment. However, sometimes there are unfavourable changes in the functioning of the brain and memory deficits occur, which may be associated with various diseases. Disturbances in the cholinergic system lead to abnormalities in memory functioning and are an essential part of clinical symptoms of many neurodegenerative diseases. However, their treatment is difficult and still unsatisfactory; thus, it is necessary to search for new drugs and their targets, being an alternative method of mono- or polypharmacotherapy. One of the possible strategies for the modulation of memory-related cognitive disorders is connected with the endocannabinoid system (ECS). The aim of the present study was to determine for the first time the effect of administration of natural cannabinoid compound (cannabidiol, CBD) and rivastigmine alone and in combination on the memory disorders connected with cholinergic dysfunctions in mice, provoked by using an antagonist of muscarinic cholinergic receptor-scopolamine. To assess and understand the memory-related effects in animals, we used the passive avoidance (PA) test, commonly used to examine the different stages of memory. An acute administration of CBD (1 mg/kg) or rivastigmine (0.5 mg/kg) significantly affected changes in scopolamine-induced disturbances in three different memory stages (acquisition, consolidation, and retrieval). Interestingly, co-administration of CBD (1 mg/kg) and rivastigmine (0.5 mg/kg) also attenuated memory impairment provoked by scopolamine (1 mg/kg) injection in the PA test in mice, but at a much greater extent than administered alone. The combination therapy of these two compounds, CBD and rivastigmine, appears to be more beneficial than substances administered alone in reducing scopolamine-induced cognitive impairment. This polytherapy seems to be favourable in the pharmacotherapy of various cognitive disorders, especially those in which cholinergic pathways are implicated.
PubMed: 38931476
DOI: 10.3390/ph17060809 -
PloS One 2024Myopia, characterized by excessive axial elongation of the eyeball, increases risks of having sight-threatening diseases and impose a financial burden to healthcare... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Myopia, characterized by excessive axial elongation of the eyeball, increases risks of having sight-threatening diseases and impose a financial burden to healthcare system. Although myopic control interventions showed their effectiveness in slowing progression, the efficacy varies between individuals and does not completely halt progression. The study aims to investigate the efficacy of combining 0.01% atropine administered twice daily with optical defocus for myopia control in schoolchildren.
METHODS AND DESIGN
This is a prospective, parallel-group, single-blinded, randomized, active-control trial (ClinicalTrials.gov identifier: NCT06358755). Myopic schoolchildren with no previous myopic control interventions aged between 7 to 12 years will be recruited. They will be randomly allocated into two groups (n = 56 per group) after baseline measurement. Both groups will receive 0.01% atropine twice per day for 18 months (one drop in the morning and the other drop at night before bedtime). Defocus incorporated multiple segments (DIMS) spectacle lenses will be prescribed in atropine plus optical defocus (ATD) treatment group while single vision spectacle lenses will be given in atropine only (AT) group. Cycloplegic refraction and axial lengths will be monitored every 6 months over 18-month study period. The primary outcomes are changes in cycloplegic refraction and axial lengths relative to the baseline over the study period.
DISCUSSION
The result will examine the combination effect of low dose atropine and myopic defocus on myopia control in a randomized controlled study. The findings will also explore the potential benefits of applying 0.01% atropine twice per day on myopic control and its potential side effects.
Topics: Humans; Atropine; Myopia; Child; Prospective Studies; Male; Female; Refraction, Ocular; Eyeglasses; Single-Blind Method; Ophthalmic Solutions; Mydriatics; Treatment Outcome
PubMed: 38923965
DOI: 10.1371/journal.pone.0306050 -
Scientific Reports Jun 2024Head-fixation of mice enables high-resolution monitoring of neuronal activity coupled with precise control of environmental stimuli. Virtual reality can be used to...
Head-fixation of mice enables high-resolution monitoring of neuronal activity coupled with precise control of environmental stimuli. Virtual reality can be used to emulate the visual experience of movement during head fixation, but a low inertia floating real-world environment (mobile homecage, MHC) has the potential to engage more sensory modalities and provide a richer experimental environment for complex behavioral tasks. However, it is not known whether mice react to this adapted environment in a similar manner to real environments, or whether the MHC can be used to implement validated, maze-based behavioral tasks. Here, we show that hippocampal place cell representations are intact in the MHC and that the system allows relatively long (20 min) whole-cell patch clamp recordings from dorsal CA1 pyramidal neurons, revealing sub-threshold membrane potential dynamics. Furthermore, mice learn the location of a liquid reward within an adapted T-maze guided by 2-dimensional spatial navigation cues and relearn the location when spatial contingencies are reversed. Bilateral infusions of scopolamine show that this learning is hippocampus-dependent and requires intact cholinergic signalling. Therefore, we characterize the MHC system as an experimental tool to study sub-threshold membrane potential dynamics that underpin complex navigation behaviors.
Topics: Animals; Mice; Spatial Navigation; Maze Learning; Male; Hippocampus; Pyramidal Cells; Mice, Inbred C57BL; Membrane Potentials; CA1 Region, Hippocampal; Virtual Reality; Scopolamine; Patch-Clamp Techniques
PubMed: 38906952
DOI: 10.1038/s41598-024-64807-w -
BioRxiv : the Preprint Server For... Jun 2024Oxybutynin (Ditropan), a widely distributed muscarinic antagonist for treating the overactive bladder, has been awaiting a definitive crystal structure for nearly 50...
Oxybutynin (Ditropan), a widely distributed muscarinic antagonist for treating the overactive bladder, has been awaiting a definitive crystal structure for nearly 50 years due to the sample and technique limitations. Past reports used powder X-ray diffraction (PCRD) to shed light on the possible packing of the molecule however a 3D structure remained elusive. Here we used Microcrystal Electron Diffraction (MicroED) to successfully unveil the 3D structure of oxybutynin hydrochloride. We identify several inconsistencies between the reported PXRD analyses and the experimental structure. Using the improved model, molecular docking was applied to investigate the binding mechanism between M muscarinic receptor (MR) and ()-oxybutynin, revealing essential contacts/residues and conformational changes within the protein pocket. A possible universal conformation was proposed for MR antagonists, which is valuable for future drug development and optimization. This study underscores the immense potential of MicroED as a complementary technique for elucidating the unknown pharmaceutical crystal structures, as well as for the protein-drug interactions.
PubMed: 38895300
DOI: 10.1101/2024.06.05.597682 -
International Journal of Molecular... May 2024Organophosphoate (OP) chemicals are known to inhibit the enzyme acetylcholinesterase (AChE). Studying OP poisoning is difficult because common small animal research...
Organophosphoate (OP) chemicals are known to inhibit the enzyme acetylcholinesterase (AChE). Studying OP poisoning is difficult because common small animal research models have serum carboxylesterase, which contributes to animals' resistance to OP poisoning. Historically, guinea pigs have been used for this research; however, a novel genetically modified mouse strain (KIKO) was developed with nonfunctional serum carboxylase (Es1 KO) and an altered acetylcholinesterase (AChE) gene, which expresses the amino acid sequence of the human form of the same protein (AChE KI). KIKO mice were injected with 1xLD of an OP nerve agent or vehicle control with or without atropine. After one to three minutes, animals were injected with 35 mg/kg of the currently fielded Reactivator countermeasure for OP poisoning. Postmortem brains were imaged on a Bruker RapifleX ToF/ToF instrument. Data confirmed the presence of increased acetylcholine in OP-exposed animals, regardless of treatment or atropine status. More interestingly, we detected a small amount of Reactivator within the brain of both exposed and unexposed animals; it is currently debated if reactivators can cross the blood-brain barrier. Further, we were able to simultaneously image acetylcholine, the primary affected neurotransmitter, as well as determine the location of both Reactivator and acetylcholine in the brain. This study, which utilized sensitive MALDI-MSI methods, characterized KIKO mice as a functional model for OP countermeasure development.
Topics: Animals; Organophosphate Poisoning; Mice; Disease Models, Animal; Humans; Acetylcholinesterase; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Atropine; Brain; Mice, Knockout; Cholinesterase Inhibitors; Acetylcholine
PubMed: 38891812
DOI: 10.3390/ijms25115624 -
ERJ Open Research May 2024COPD is a major healthcare problem and cause of mortality worldwide. COPD patients at increased mortality risk are those who are more symptomatic, have lower lung... (Review)
Review
COPD is a major healthcare problem and cause of mortality worldwide. COPD patients at increased mortality risk are those who are more symptomatic, have lower lung function and lower diffusing capacity of the lung for carbon monoxide, decreased exercise capacity, belong to the emphysematous phenotype and those who have concomitant bronchiectasis. Mortality risk seems to be greater in patients who experience COPD exacerbations and in those who suffer from concomitant cardiovascular and/or metabolic diseases. To predict the risk of death in COPD patients, several composite scores have been created using different parameters. In previous years, large studies (also called mega-trials) have evaluated the efficacy of different therapies on COPD mortality, but until recently only nonpharmaceutical interventions have proven to be effective. However, recent studies on fixed combinations of triple therapy (long-acting β-agonists, long-acting muscarinic antagonists and inhaled corticosteroids) have provided encouraging results, showing for the first time a reduction in mortality compared to dual therapies. The aim of the present review is to summarise available data regarding mortality risk in COPD patients and to describe pharmacological therapies that have shown effectiveness in reducing mortality.
PubMed: 38887682
DOI: 10.1183/23120541.00850-2023 -
The Korean Journal of Pain Jun 2024has bioactive constituents and has been used for therapeutic actions. The present study was undertaken to investigate the mechanisms underlying pain-relieving effects...
BACKGROUND
has bioactive constituents and has been used for therapeutic actions. The present study was undertaken to investigate the mechanisms underlying pain-relieving effects of the hydroethanolic extract of C. scolymus (HECS).
METHODS
The antinociceptive activity of HECS was assessed through formalin and acetic acid-induced writhing tests at doses of 50, 100 and 200 mg/kg intraperitoneally. Additionally, naloxone (non-selective opioid receptors antagonist, 2 mg/kg), atropine (non-selective muscarinic receptors antagonist, 1 mg/kg), chlorpheniramine (histamine HH-receptor antagonist, 20 mg/kg), cimetidine (histamine H-receptor antagonist, 12.5 mg/kg), flumazenil (GABA/BDZ receptor antagonist, 5 mg/kg) and cyproheptadine (serotonin receptor antagonist, 4 mg/kg) were used to determine the systis implicated in HECS-induced analgesia. Impact of HECS on locomotor activity was executed by open-field test. Determination of total phenolic content (TPC) and total flavonoid content (TFC) was done. Evaluation of antioxidant activity was conducted iploying 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay.
RESULTS
HECS (50, 100 and 200 mg/kg) significantly indicated dose dependent antinociceptive activity against pain-related behavior induced by formalin and acetic acid ( < 0.001). Pretreatment with naloxone, atropine and flumazenil significantly reversed HECS-induced analgesia. Antinociceptive effect of HECS riained unaffected by chlorpheniramine, cimetidine and cyproheptadine. Locomotor activity was not affected by HECS. TPC and TFC of HECS were 59.49 ± 5.57 mgGAE/g dry extract and 93.39 ± 17.16 mgRE/g dry extract, respectively. DPPH free radical scavenging activity (IC) of HECS was 161.32 ± 0.03 μg/mL.
CONCLUSIONS
HECS possesses antinociceptive activity which is mediated via opioidergic, cholinergic and GABAergic pathways.
PubMed: 38881282
DOI: 10.3344/kjp.23355 -
Therapeutic Advances in Respiratory... 2024Some systematic reviews (SRs) on triple therapy (consisting of long-acting β-agonist, long-acting muscarinic antagonist, and inhaled corticosteroid, LABA/LAMA/ICS) for...
BACKGROUND
Some systematic reviews (SRs) on triple therapy (consisting of long-acting β-agonist, long-acting muscarinic antagonist, and inhaled corticosteroid, LABA/LAMA/ICS) for chronic obstructive pulmonary disease (COPD) have reported conflicting results. As the number of syntheses increases, the task of identifying and interpreting evidence becomes increasingly complex and demanding.
OBJECTIVES
To provide a comprehensive overview of the efficacy and safety of triple therapy for COPD.
DESIGN
Overview of SRs.
METHODS
Two independent reviewers conducted comprehensive searches in PubMed, Embase, Web of Science, and the Cochrane Library to identify relevant SRs that compared triple therapy with any non-triple therapy for COPD, from the inception of these databases until 1 June 2023. The AMSTAR 2 and GRADE tools were utilized to assess the quality of the included studies and the evidence for each outcome.
RESULTS
Eighteen SRs encompassing 30 original studies and involving 47,340 participants were analyzed. The overall AMSTAR 2 rating revealed that 3 SRs were of low quality, 13 SRs were of critically low quality, and 2 SRs were of high quality. No high-certainty evidence revealed a significant advantage of triple therapy in improving lung function or reducing acute exacerbations. However, all evidence, including one high certainty, supported the benefits of improving quality of life. Regarding all-cause mortality, no significant difference was found when compared to LAMA or ICS/LABA; however, high-certainty evidence confirmed its effectiveness when compared with LABA/LAMA. Notably, high-certainty evidence indicated that triple therapy was associated with a significant increase in the risk of pneumonia compared to LABA/LAMA.
CONCLUSION
Triple therapy demonstrated notable benefits in improving lung function, reducing exacerbations, improving quality of life, and reducing all-cause mortality. However, it is important to note that it may also significantly increase the risk of pneumonia.
TRIAL REGISTRATION
This overview protocol was prospectively registered with PROSPERO (No. CRD42023431548).
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Systematic Reviews as Topic; Drug Therapy, Combination; Muscarinic Antagonists; Treatment Outcome; Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Adrenal Cortex Hormones; Bronchodilator Agents; Lung; Quality of Life
PubMed: 38877687
DOI: 10.1177/17534666241259634 -
Medicine Jun 2024It aims to study the efficacy and safety of low-concentration Atropine combined with orthokeratology (OK) lens in delaying juvenile myopia. This is a prospective study,... (Observational Study)
Observational Study Randomized Controlled Trial
It aims to study the efficacy and safety of low-concentration Atropine combined with orthokeratology (OK) lens in delaying juvenile myopia. This is a prospective study, 172 adolescents aged 8 to 12 years who were admitted to the diopter department of Hengshui People Hospital from April 2021 to May 2022 were selected. According to the equivalent spherical diopter measured at the time of initial diagnosis, myopic patients were randomly divided into low myopia group (group A) and moderate myopia group (group B). At the same time, according to the different treatment methods, the patients were divided into the group wearing frame glasses alone (group c), the group wearing frame glasses with low-concentration Atropine (group d), the group wearing corneal shaping glasses alone at night (group e), and the group wearing corneal shaping glasses at night with low-concentration Atropine (group f). The control effect of myopia development and axial elongation in group f was better than that in groups d and e (P < .05). The effect of controlling myopia development and axial elongation in group f is with P > .05. The probability of postoperative adverse reactions in group f was lower and lower than that in the other groups. Low-concentration atropine combined with OK lens could effectively delay the development of juvenile myopia, and had a high safety. Low-concentration of Atropine would not have a significant impact on the basic tear secretion and tear film stability. Nightwear of OK lens also had no significant impact, but it would significantly reduce the tear film rupture time in the first 3 months, and at the same time, the tear film rupture time would be the same after 6 months as before treatment.
Topics: Humans; Atropine; Child; Myopia; Male; Female; Orthokeratologic Procedures; Prospective Studies; Mydriatics; Treatment Outcome; Ophthalmic Solutions; Contact Lenses
PubMed: 38875374
DOI: 10.1097/MD.0000000000038384 -
PloS One 2024This study aimed to define real-world prescription patterns in Korea and compare the effectiveness of chronic obstructive pulmonary disease (COPD) medications. We used...
This study aimed to define real-world prescription patterns in Korea and compare the effectiveness of chronic obstructive pulmonary disease (COPD) medications. We used national claims data provided by the Health Insurance Review and Assessment Service in Korea and examined patients who were first diagnosed with COPD and started treatment between May 1, 2017, and April 30, 2018, with no change in drug regimen. Among 30,784 patients with COPD, long-acting β2 agonist (LABA) combined with long-acting muscarinic antagonist (LAMA) (32.7%), inhaled corticosteroid-LABA (ICS-LABA) (25.6%), LAMA (18.3%), ICS (5.8%), or LABA (4.6%) were prescribed as the first-choice inhalers. The use of LABA-LAMA (hazard ratio [HR], 0.248-0.584), LAMA (HR, 0.320-0.641), ICS-LABA (HR, 0.325-0.643), and xanthine (HR, 0.563-0.828) significantly reduced the total and severe exacerbation rates compared with no use of each medication. However, the use of ICS or LABA individually did not yield such effects. The continued use of LABA-LAMA, LAMA, and ICS-LABA showed a significant effect on exacerbation rate, whereas the long-term use of ICS, LABA, and xanthine did not. Moreover, some high doses of ICS-LABA did not show significant effects. This real-world study revealed that LAMA and/or LABA could be the first choice of therapy, as recommended by recent guidelines. However, ICS, xanthine, and high-dose ICS-LABA are still being prescribed frequently as first-line drugs in Korea.
Topics: Pulmonary Disease, Chronic Obstructive; Humans; Male; Female; Retrospective Studies; Aged; Middle Aged; Muscarinic Antagonists; Republic of Korea; Adrenergic beta-2 Receptor Agonists; Administration, Inhalation; Adrenal Cortex Hormones; Practice Patterns, Physicians'; Treatment Outcome; Bronchodilator Agents; Drug Prescriptions; Adult
PubMed: 38857214
DOI: 10.1371/journal.pone.0304362