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International Journal of Molecular... Mar 2024The beneficial effects of increasing histamine levels on memory have acquired special interest due to their applicability to psychiatric conditions that cause memory...
The beneficial effects of increasing histamine levels on memory have acquired special interest due to their applicability to psychiatric conditions that cause memory impairments. In addition, by employing drug repurposing approaches, it was demonstrated that dihydroergotamine (DHE), an FDA drug approved to treat migraines, inhibits Histamine N Methyl Transferase (HNMT), the enzyme responsible for the inactivation of histamine in the brain. For this reason, in the present work, the effect of DHE on histamine levels in the hippocampus and its effects on memory was evaluated, employing the scopolamine-induced amnesia model, the Novel Object Recognition (NOR) paradigm, and the Morris Water Maze (MWM). Furthermore, the role of histamine 1 receptor (H1R) and histamine 2 receptor (H2R) antagonists in the improvement in memory produced by DHE in the scopolamine-induced amnesia model was evaluated. Results showed that the rats that received DHE (10 mg/kg, i.p.) showed increased histamine levels in the hippocampus after 1 h of administration but not after 5 h. In behavioral assays, it was shown that DHE (1 mg/kg, i.p.) administered 20 min before the training reversed the memory impairment produced by the administration of scopolamine (2 mg/kg, i.p.) immediately after the training in the NOR paradigm and MWM. Additionally, the effects in memory produced by DHE were blocked by pre-treatment with pyrilamine (20 mg/kg, i.p.) administered 30 min before the training in the NOR paradigm and MWM. These findings allow us to demonstrate that DHE improves memory in a scopolamine-induced amnesia model through increasing histamine levels at the hippocampus due to its activity as an HNMT inhibitor.
Topics: Animals; Rats; Scopolamine; Dihydroergotamine; Histamine; Amnesia; Brain; Memory Disorders; Histamine H2 Antagonists
PubMed: 38612521
DOI: 10.3390/ijms25073710 -
Journal of Veterinary Internal Medicine 2024Salbutamol and hyoscine butylbromide (HBB) are commonly used bronchodilators in horses with severe asthma (SA). (Comparative Study)
Comparative Study
BACKGROUND
Salbutamol and hyoscine butylbromide (HBB) are commonly used bronchodilators in horses with severe asthma (SA).
OBJECTIVE
To compare the bronchodilation potency, duration, and adverse effects of salbutamol and HBB in SA.
ANIMALS
Six horses in exacerbation of SA.
METHODS
The effects of inhaled salbutamol (1000 μg) and HBB (150 mg, IV) were compared in a randomized, blinded, crossover experiment. Lung function, intestinal borborygmi and heart rate were assessed before and sequentially until 180 minutes after drug administration, and analyzed with 2-way repeated-measures ANOVA and Dunnett's multiple comparison tests.
RESULTS
Both treatments caused a similar improvement in lung function. Pulmonary resistance and reactance returned to baseline values within 30 minutes after HBB administration, whereas salbutamol improved reactance until 180 minutes (mean improvement at 180 minutes of 0.040 Kpa/L/s, 95% CI = 0.004 to 0.076; P = .02 for salbutamol and of 0.009 Kpa/L/s, 95% CI = -0.028 to 0.045; P = .98 for HBB for the resistance at 3 Hz and of 0.040 Kpa/L/s, 95% CI = 0.007 to 0.074; P = .01 for salbutamol and of 0.009 Kpa/L/s, 95% CI = -0.024 to 0.042; P = .97 for HBB for the reactance at 7 Hz). From 5 to 30 minutes after HBB administration, the heart rate accelerated (mean increase of 3.3 beats per minute, 95% CI = -6.6 to 13.1; P = .92 for salbutamol, and of 13.0 beats per minute, 95% CI = 3.6 to 22.4; P = .002 for HBB at 30 minutes) and the gut sounds decreased (mean reduction of 1.3, 95% CI = -0.1 to 2.8; P = .09 for salbutamol and of 2.8 for the gastrointestinal auscultation score, 95% CI = 1.4 to 4.3; P < .0001 for HBB at 30 minutes).
CONCLUSIONS AND CLINICAL IMPORTANCE
Both drugs have a similar bronchodilator potency but with a longer duration for salbutamol. Gastrointestinal and cardiovascular effects were noted only with HBB, suggesting the preferential use of salbutamol to relieve bronchoconstriction in horses with asthma.
Topics: Animals; Horses; Albuterol; Asthma; Horse Diseases; Bronchodilator Agents; Cross-Over Studies; Butylscopolammonium Bromide; Male; Female; Heart Rate; Administration, Inhalation
PubMed: 38609079
DOI: 10.1111/jvim.17057 -
Drug Metabolism and Pharmacokinetics Jun 2024To assess the pharmacologically relevant and selective muscarinic receptor occupancy in the bladder mucosa, we considered not only plasma drug concentrations but also...
To assess the pharmacologically relevant and selective muscarinic receptor occupancy in the bladder mucosa, we considered not only plasma drug concentrations but also urinary drug concentrations. The purpose of this study was to predict muscarinic receptor occupancy in the human bladder mucosa based on urinary concentrations in response to clinical dosages of antimuscarinic agents used to treat overactive bladder. The calculated mean plasma or serum unbound steady state concentrations were 0.06-11 nM in clinical dosages of five antimuscarinic agents. Urinary concentrations calculated from the mean plasma or serum and renal clearance ranged between 19 nM and 2 μM, which were >10-fold higher than the K values for bladder muscarinic receptors excluding propiverine. Bladder mucosal muscarinic receptor occupancy estimated from the urinary concentrations and the K values was >90 % at a steady state in clinical dosages of five antimuscarinic agents. The bladder muscarinic receptor occupancy was higher than that in the parotid gland calculated based on the mean plasma or serum unbound concentrations and K values for muscarinic receptors in the parotid gland. These results suggest that sufficient and selective muscarinic receptor occupancy by antimuscarinic agents, to exert pharmacological effects, in the bladder mucosa can be predicted using urinary concentrations.
Topics: Humans; Muscarinic Antagonists; Urinary Bladder, Overactive; Receptors, Muscarinic; Urinary Bladder; Mucous Membrane; Male; Female; Middle Aged; Adult; Aged
PubMed: 38583388
DOI: 10.1016/j.dmpk.2024.100998 -
Biomedicine & Pharmacotherapy =... May 2024A novel small molecule based on benzothiazole-piperazine has been identified as an effective multi-target-directed ligand (MTDL) against Alzheimer's disease (AD)....
A novel small molecule based on benzothiazole-piperazine has been identified as an effective multi-target-directed ligand (MTDL) against Alzheimer's disease (AD). Employing a medicinal chemistry approach, combined with molecular docking, MD simulation, and binding free energy estimation, compound 1 emerged as a potent MTDL against AD. Notably, compound 1 demonstrated efficient binding to both AChE and Aβ1-42, involving crucial molecular interactions within their active sites. It displayed a binding free energy (ΔG) -18.64± 0.16 and -16.10 ± 0.18 kcal/mol against AChE and Aβ1-42, respectively. In-silico findings were substantiated through rigorous in vitro and in vivo studies. In vitro analysis confirmed compound 1 (IC=0.42 μM) as an effective, mixed-type, and selective AChE inhibitor, binding at both the enzyme's catalytic and peripheral anionic sites. Furthermore, compound 1 demonstrated a remarkable ability to reduce the aggregation propensity of Aβ, as evidenced by Confocal laser scanning microscopy and TEM studies. Remarkably, in vivo studies exhibited the promising therapeutic potential of compound 1. In a scopolamine-induced memory deficit mouse model of AD, compound 1 showed significantly improved spatial memory and cognition. These findings collectively underscore the potential of compound 1 as a promising therapeutic candidate for the treatment of AD.
Topics: Alzheimer Disease; Animals; Benzothiazoles; Molecular Docking Simulation; Cholinesterase Inhibitors; Amyloid beta-Peptides; Acetylcholinesterase; Mice; Male; Humans; Piperazines; Scopolamine; Piperazine; Peptide Fragments; Molecular Dynamics Simulation; Computer Simulation; Disease Models, Animal; Maze Learning
PubMed: 38565058
DOI: 10.1016/j.biopha.2024.116484 -
BMC Anesthesiology Apr 2024Glycopyrrolate-neostigmine (G/N) for reversing neuromuscular blockade (NMB) causes fewer changes in heart rate (HR) than atropine-neostigmine (A/N). This advantage may... (Randomized Controlled Trial)
Randomized Controlled Trial
The effect of glycopyrrolate vs. atropine in combination with neostigmine on cardiovascular system for reversal of residual neuromuscular blockade in the elderly: a randomized controlled trial.
BACKGROUND
Glycopyrrolate-neostigmine (G/N) for reversing neuromuscular blockade (NMB) causes fewer changes in heart rate (HR) than atropine-neostigmine (A/N). This advantage may be especially beneficial for elderly patients. Therefore, this study aimed to compare the cardiovascular effects of G/N and A/N for the reversal of NMB in elderly patients.
METHODS
Elderly patients aged 65-80 years who were scheduled for elective non-cardiac surgery under general anesthesia were randomly assigned to the glycopyrrolate group (group G) or the atropine group (group A). Following the last administration of muscle relaxants for more than 30 min, group G received 4 ug/kg glycopyrrolate and 20 ug/kg neostigmine, while group A received 10 ug/kg atropine and 20 ug/kg neostigmine. HR, mean arterial pressure (MAP), and ST segment in lead II (ST-II) were measured 1 min before administration and 1-15 min after administration.
RESULTS
HR was significantly lower in group G compared to group A at 2-8 min after administration (P < 0.05). MAP was significantly lower in group G compared to group A at 1-4 min after administration (P < 0.05). ST-II was significantly depressed in group A compared to group G at 2, 3, 4, 5, 6, 7, 8, 9, 11, 13, 14, and 15 min after administration (P < 0.05).
CONCLUSIONS
In comparison to A/N, G/N for reversing residual NMB in the elderly has a more stable HR, MAP, and ST-II within 15 min after administration.
Topics: Aged; Humans; Neostigmine; Glycopyrrolate; Atropine; Delayed Emergence from Anesthesia; Neuromuscular Blockade; Cardiovascular System
PubMed: 38561654
DOI: 10.1186/s12871-024-02512-x -
Prostate Cancer and Prostatic Diseases Jun 2024Low-intensity shockwave therapy (Li-SWT) can improve bladder function through enhancement of angiogenesis and nerve regeneration and suppression of inflammation and... (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized controlled trial evaluating low-intensity shockwave therapy for treatment of persistent storage symptoms following transurethral surgery for benign prostatic obstruction.
BACKGROUND
Low-intensity shockwave therapy (Li-SWT) can improve bladder function through enhancement of angiogenesis and nerve regeneration and suppression of inflammation and overactivity. In this trial, we aimed to evaluate the efficacy of Li-SWT on persistent storage symptoms after transurethral surgery (TUS) for benign prostatic obstruction (BPO).
METHODS
Between July 2020 and July 2022, 137 patients with persistent storage symptoms; urgency episodes/24 h ≥ 1 and daytime frequency ≥8, for at least three months after TUS for BPO were randomly allocated to Li-SWT versus sham versus solifenacin 10 mg/day in 3:1:1 ratio. The primary end point was the percent reduction from baseline in overactive bladder symptom score (OABSS) at 3-month follow-up. The changes in 3-day voiding diary parameters, quality of life (QoL) score, peak flow rate and residual urine at 3 and 6-month follow-up were compared. Treatment-related adverse effects were also evaluated.
RESULTS
Baseline data were comparable between groups. The percent reduction from baseline in OABSS at 3-month follow-up was significantly higher in Li-SWT compared to sham (-55% versus -11%), and it was comparable between Li-SWT and solifenacin-10 (-55% versus -60%). Li-SWT achieved significant improvement like solifenacin-10 in 3-day voiding diary parameters and QoL score at 3-month follow-up. This improvement remained comparable between Li-SWT and solifenacin-10 at 6-month follow-up. No adverse effects related to Li-SWT were noted apart from tolerable pain during the procedure. Solifenacin-10 was associated with bothersome adverse effects in 73% of the patients with 11.5% discontinuation rate.
CONCLUSIONS
Li-SWT ameliorates persistent storage symptoms and promotes QoL after TUS for BPO, with comparable efficacy and better tolerance compared to solifenacin.
Topics: Humans; Male; Aged; Transurethral Resection of Prostate; Prostatic Hyperplasia; Quality of Life; Middle Aged; Solifenacin Succinate; Treatment Outcome; Follow-Up Studies; Extracorporeal Shockwave Therapy; Urinary Bladder, Overactive; Postoperative Complications; Double-Blind Method
PubMed: 38553627
DOI: 10.1038/s41391-024-00820-4 -
Scientific Reports Mar 2024Persistence is important for the success in the treatment of women with overactive bladder syndrome (OAB). We aimed to identify the predictors of non-persistence in...
Persistence is important for the success in the treatment of women with overactive bladder syndrome (OAB). We aimed to identify the predictors of non-persistence in women with OAB after first-line medical treatment. All consecutive women with OAB (n = 608), who underwent urodynamic studies and received first-line medical treatment (5 mg of solifenacin or 25 mg of mirabegron per day) in a referral medical center, were reviewed. Mirabegron (hazard ratio [HR] = 0.711) was associated with a higher persistence rate, compared to solifenacin. Mirabegron treatment (HR = 0.269) was less likely to switch medication; however, a high Urogenital Distress Inventory score (HR = 1.082) was more likely to switch medication. Furthermore, old age (HR = 1.050, especially for ≥ 75 years) and high voided volume (dL, HR = 1.420, especially for voided volume ≥ 250 ml) were associated with added medication at follow-up. Additionally, women with low parity (HR = 0.653, especially for parity ≤ 3) and a low Incontinence Impact Questionnaire (IIQ-7) score (HR = 0.828, especially for IIQ-7 score ≤ 7) were associated with improvement without medication. In conclusion, mirabegron can be considered as the first frontline treatment to increase the persistence rate and decrease the rate of switched medications, compared to solifenacin. In addition, combination therapy or higher-dose monotherapy could be used as the first front-line treatment for women ≥ 75 years of age or with ≥ 250 ml of voided volume.
Topics: Humans; Female; Aged; Solifenacin Succinate; Urinary Bladder, Overactive; Treatment Outcome; Acetanilides; Urinary Incontinence; Muscarinic Antagonists; Thiazoles
PubMed: 38553529
DOI: 10.1038/s41598-024-58036-4 -
PLoS Medicine Mar 2024Prolonged labor is a common condition associated with maternal and perinatal complications. The standard treatment with oxytocin for augmentation of labor increases the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Prolonged labor is a common condition associated with maternal and perinatal complications. The standard treatment with oxytocin for augmentation of labor increases the risk of adverse outcomes. Hyoscine butylbromide is a spasmolytic drug with few side effects shown to shorten labor when used in a general population of laboring women. However, research on its effect on preventing prolonged labor is lacking. We aimed to assess the effect of hyoscine butylbromide on the duration of labor in nulliparous women showing early signs of slow labor.
METHODS AND FINDINGS
In this double-blind randomized placebo-controlled trial, we included 249 nulliparous women at term with 1 fetus in cephalic presentation and spontaneous start of labor, showing early signs of prolonged labor by crossing the alert line of the World Health Organization (WHO) partograph. The trial was conducted at Oslo University Hospital in Norway from May 2019 to December 2021. One hundred and twenty-five participants were randomized to receive 1 ml hyoscine butylbromide (Buscopan) (20 mg/ml), while 124 received 1 ml sodium chloride intravenously. Randomization was computer-generated, with allocation concealment by opaque sequentially numbered sealed envelopes. The primary outcome was duration of labor from administration of the investigational medicinal product (IMP) to vaginal delivery, which was analyzed by Weibull regression to estimate the cause-specific hazard ratio (HR) of vaginal delivery between the 2 treatment groups, with associated 95% confidence interval (CI). A wide range of secondary maternal and perinatal outcomes were also evaluated. Time-to-event outcomes were analyzed by Weibull regression, whereas continuous and dichotomous outcomes were analyzed by median regression and logistic regression, respectively. All main analyses were based on the modified intention-to-treat (ITT) set of eligible women with signed informed consent receiving either of the 2 treatments. The follow-up period lasted during the postpartum hospital stay. All personnel, participants, and researchers were blinded to the treatment allocation. Median (mean) labor duration from IMP administration to vaginal delivery was 401 (440.8) min in the hyoscine butylbromide group versus 432.5 (453.6) min in the placebo group. We found no statistically significant association between IMP and duration of labor from IMP administration to vaginal delivery: cause-specific HR of 1.00 (95% CI [0.77, 1.29]; p = 0.993). Among 255 randomized women having received 1 dose of IMP, 169 women (66.3%) reported a mild adverse event: 75.2% in the hyoscine butylbromide group and 57.1% in the placebo group (Pearson's chi-square test: p = 0.002). More than half of eligible women were not included in the study because they did not wish to participate or were not included upon admission. The participants might have represented a selected group of women reducing the external validity of the study.
CONCLUSIONS
One intravenous dose of 20 mg hyoscine butylbromide was not found to be superior to placebo in preventing slow labor progress in a population of first-time mothers at risk of prolonged labor. Further research is warranted to answer whether increased and/or repeated doses of hyoscine butylbromide might have an effect on duration of labor.
TRIAL REGISTRATION
ClinicalTrials.gov (NCT03961165) EudraCT (2018-002338-19).
Topics: Female; Humans; Pregnancy; Butylscopolammonium Bromide; Double-Blind Method; Hydrocarbons, Brominated; Labor, Obstetric; Parasympatholytics; Scopolamine
PubMed: 38547322
DOI: 10.1371/journal.pmed.1004352 -
Biological Psychiatry Mar 2024Achieving optimal treatment outcomes for individuals living with schizophrenia remains challenging, despite 70 years of drug development efforts. Many chemically... (Review)
Review
Achieving optimal treatment outcomes for individuals living with schizophrenia remains challenging, despite 70 years of drug development efforts. Many chemically distinct antipsychotics have been developed over the past 7 decades with improved safety and tolerability but with only slight variation in efficacy. All antipsychotics currently approved for the treatment of schizophrenia act as antagonists or partial agonists at the dopamine D receptor. With only a few possible exceptions, antipsychotic drugs have similar and modest efficacy for treating positive symptoms and are relatively ineffective in addressing the negative and cognitive symptoms of the disease. The development of novel treatments focused on targeting muscarinic acetylcholine receptors (mAChRs) has been of interest for more than 25 years following reports that treatment with a dual M/M-preferring mAChR agonist resulted in antipsychotic-like effects and procognitive properties in individuals living with Alzheimer's disease and schizophrenia; more recent clinical trials have confirmed these findings. In addition, advances in our understanding of the receptor binding and activation properties of xanomeline at specific mAChRs have the potential to inform future drug design targeting mAChRs.
PubMed: 38537670
DOI: 10.1016/j.biopsych.2024.03.014 -
Journal of Thoracic Disease Feb 2024Roflumilast is effective in reducing acute exacerbation in patients with chronic obstructive pulmonary disease (COPD) at high risk of severe exacerbation. Clinical...
BACKGROUND
Roflumilast is effective in reducing acute exacerbation in patients with chronic obstructive pulmonary disease (COPD) at high risk of severe exacerbation. Clinical traits related to the benefits of roflumilast need to be evaluated in patients with COPD.
METHODS
A longitudinal observational study in patients newly diagnosed with COPD was conducted using claims data from the Health Insurance Review and Assessment Service in South Korea from 2012-2020 after a 2-year washout period. The primary outcome was to estimate the ratio of hazard ratio (RHR) of roflumilast for moderate-to-severe exacerbation in prespecified subgroups. A time-dependent Cox regression model was used to estimate the hazard ratio (HR) for moderate-to-severe exacerbations.
RESULTS
Among 823,862 patients with COPD, 0.6% used roflumilast. The adjusted HR of roflumilast for moderate-to-severe exacerbations was reduced when treated for ≥3 months (RHR =0.558). Interaction effects of the variables on the HR of roflumilast for moderate-to-severe exacerbation were identified. The adjusted HR of roflumilast for moderate-to-severe exacerbation was significantly reduced in several subgroups: older age (65 years > age ≥50 years, RHR =0.838; age ≥65 years, RHR =0.818), a higher Charlson comorbidity index (1, RHR =0.832; 2, RHR =0.798; ≥3, RHR =0.790), history of exacerbation (RHR =0.886), bronchiectasis (RHR =0.774), chronic bronchitis (RHR =0.793), inhaled therapy [mono-bronchodilator, RHR =0.824; inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA), RHR =0.591; LABA/long-acting muscarinic antagonist (LAMA), RHR =0.822; ICS/LABA/LAMA, RHR =0.570], methylxanthine (RHR =0.853), and statin (RHR =0.888).
CONCLUSIONS
The benefit of roflumilast in moderate-to-severe exacerbations was estimated to be greater in specific subgroups of patients with COPD. Personalised approaches to roflumilast based on clinical phenotypes would be effective for COPD.
PubMed: 38505074
DOI: 10.21037/jtd-23-1129