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Human Psychopharmacology Nov 2019The objectives of this study were primarily to assess the efficacy and safety of SM-1 in a circadian challenge model of transient insomnia and secondarily, to assess the... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
The objectives of this study were primarily to assess the efficacy and safety of SM-1 in a circadian challenge model of transient insomnia and secondarily, to assess the contribution of diphenhydramine to the combination.
METHODS
Randomized, double-blind, placebo-controlled three-way cross-over study with a 5-hr phase advance. Subjects were 39 healthy adults reporting a history of transient insomnia. All treatments (SM-1, SM-1 without diphenhydramine, or placebo) were administered to all subjects in a randomly assigned sequence, with at least 1 week between treatments. The primary endpoint was total sleep time (TST) determined by polysomnography. Secondary endpoints included wakefulness after sleep onset (WASO), latency to persistent sleep, number of awakenings (NAW), subjective TST (sTST) and sleep latency (sSL), TST, and NAW by quarters of the night and sleep quality. Safety endpoints included adverse events, Karolinska Sleepiness Scale digit symbol substitution test, and subject-reported alertness level.
RESULTS
SM-1 provided an increase of 126.7 min in TST over placebo (p < .001). WASO, sTST, sleep quality, and sSL also showed significant improvement. Diphenhydramine demonstrated a significant (p = .014) contribution of 43.7 min to TST. SM-1 was well-tolerated with type and frequency of adverse events comparable with placebo, and no residual sleepiness upon awakening after 8 hr.
CONCLUSIONS
SM-1 provided a robust and statistically significant increase in TST compared with placebo in a circadian model of transient insomnia, without evidence of next-day impairment. Diphenhydramine contributed to the effect.
Topics: Adult; Cross-Over Studies; Diphenhydramine; Double-Blind Method; Drug Combinations; Female; Humans; Hypnotics and Sedatives; Lorazepam; Male; Middle Aged; Polysomnography; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Zolpidem
PubMed: 31837050
DOI: 10.1002/hup.2713 -
Physiological Reports Oct 2020Reports of the stimulated release of extracellular vesicles (EVs) are few, and the mechanisms incompletely understood. To our knowledge, the possibility that the...
Reports of the stimulated release of extracellular vesicles (EVs) are few, and the mechanisms incompletely understood. To our knowledge, the possibility that the activation of any one of the multitudes of G-protein-coupled receptors (GPCRs) expressed by a single cell-type might increase EV release has not been explored. Recently, we identified the expression of cholecystokinin (CCK), gastrin, gastrin/cholecystokinin types A and/or B receptors (CCKAR and/or -BR), and the bitter taste receptor, TAS2R14 in the human and mouse placenta. specifically, trophoblast. These GPCR(s) were also expressed in four different human trophoblast cell lines. The current objective was to employ two of these cell lines-JAR choriocarcinoma cells and HTR-8/SVneo cells derived from first-trimester human villous trophoblast-to investigate whether CCK, TAS2R14 agonists, and other GPCR ligands would each augment EV release. EVs were isolated from the cell-culture medium by filtration and ultracentrifugation. The preparations were enriched in small EVs (<200 nm) as determined by syntenin western blot before and after sucrose gradient purification, phycoerythrin (PE)-ADAM10 antibody labeling, and electron microscopy. Activation of TAS2R14, CCKBR, cholinergic muscarinic 1 & 3, and angiotensin II receptors, each increased EV release by 4.91-, 2.79-, 1.87-, and 3.11-fold, respectively (all p < .05 versus vehicle controls), without significantly changing EV diameter. A progressive increase of EV concentration in conditioned medium was observed over 24 hr consistent with the release of preformed EVs and de novo biogenesis. Compared to receptor-mediated stimulation, EV release by the calcium ionophore, A23187, was less robust (1.63-fold, p = .08). Diphenhydramine, a TAS2R14 agonist, enhanced EV release in JAR cells at a concentration 10-fold below that required to increase intracellular calcium. CCK activation of HTR-8/SVneo cells, which did not raise intracellular calcium, increased EV release by 2.06-fold (p < .05). Taken together, these results suggested that other signaling pathways may underlie receptor-stimulated EV release besides, or in addition to, calcium. To our knowledge, the finding that the activation of multiple GPCRs can stimulate EV release from a single cell-type is unprecedented and engenders a novel thesis that each receptor may orchestrate intercellular communication through the release of EVs containing a subset of unique cargo, thus mobilizing a specific integrated physiological response by a network of neighboring and distant cells.
Topics: Calcium; Cell Line, Tumor; Cholecystokinin; Diphenhydramine; Extracellular Vesicles; Flufenamic Acid; Humans; Receptors, Cholecystokinin; Receptors, G-Protein-Coupled; Trophoblasts
PubMed: 33080118
DOI: 10.14814/phy2.14592 -
Sudebno-meditsinskaia Ekspertiza 2023The purpose of this review is to study the causes of cross-reactions of a number of drugs (mebeverine, phenibut, tropicamide, ramipril, metoprolol, phenylephrine,... (Review)
Review
The purpose of this review is to study the causes of cross-reactions of a number of drugs (mebeverine, phenibut, tropicamide, ramipril, metoprolol, phenylephrine, sertraline, chloropyramine and diphenhydramine) during the preliminary stage of laboratory diagnostics by immunochromatographic method and to propose a possible algorithm for solving this problem. Conducting a hair study in order to identify the fact of the use of psychoactive substances will increase the reliability of analytical diagnostics and reduce the likelihood of false positive results of the analysis. The use of a validated method of enzymatic hydrolysis of hair will eliminate unreliable results of the analysis due to the detection of the native molecule of the toxicant, increase the efficiency and accuracy of the diagnostic procedure.
Topics: Reproducibility of Results; Metoprolol; Ramipril; Phenylephrine; Hair
PubMed: 36719313
DOI: 10.17116/sudmed20236601143 -
Drug Discoveries & Therapeutics Nov 2022Cetirizine, a second-generation antihistamine, and diphenhydramine, a first-generation antihistamine, are among the most widely used anti-allergic drugs. In addition to...
Cetirizine, a second-generation antihistamine, and diphenhydramine, a first-generation antihistamine, are among the most widely used anti-allergic drugs. In addition to longer duration of action and less incidence of sedative side effects, recent clinical studies also indicate a higher potency of cetirizine than diphenhydramine in the treatment or prevention of allergic disorders. In the present study, using the differential-interference contrast (DIC) microscopy, we examined the effects of cetirizine and diphenhydramine (1 μM to 1 mM) on the degranulation from rat peritoneal mast cells. Using fluorescence imaging of a water-soluble dye, lucifer yellow, we also examined their effects on the deformation of the plasma membrane. At relatively higher concentrations (100 μM, 1 mM), both cetirizine and diphenhydramine significantly reduced the numbers of degranulating mast cells. Of note, at 1 mM, cetirizine more markedly reduced the number than diphenhydramine, almost entirely suppressing the degranulation of mast cells. Additionally, 1 mM cetirizine and levocetirizine, another second-generation antihistamine, almost totally inhibited the process of exocytosis in mast cells and washed out the trapping of the lucifer yellow on the cell surface, while diphenhydramine and chlorpheniramine, another first-generation antihistamine, did not. This study provided in vitro evidence for the first time that cetirizine more potently inhibited the process of exocytosis in mast cells than diphenhydramine, indicating its higher potency as a mast cell-stabilizer. Such mast cell-stabilizing property of cetirizine could be ascribed to its counteracting effect on the plasma membrane deformation in degranulating mast cells.
Topics: Rats; Animals; Cetirizine; Diphenhydramine; Mast Cells; Histamine H1 Antagonists; Anti-Allergic Agents
PubMed: 36261390
DOI: 10.5582/ddt.2022.01067 -
Medicine Sep 2022Airway neutrophilia has been associated with asthma severity and asthma exacerbations. This study attempted to identify biomarkers, pathogenesis, and therapeutic...
BACKGROUND
Airway neutrophilia has been associated with asthma severity and asthma exacerbations. This study attempted to identify biomarkers, pathogenesis, and therapeutic molecular targets for severe asthma in neutrophils using bioinformatics analysis.
METHODS
Fifteen healthy controls and 3 patients with neutrophilic severe asthma were screened from the Gene Expression Omnibus (GEO) database. Based on the analysis of differentially expressed genes (DEGs), functional and pathway enrichment analyses, gene set enrichment analysis, protein-protein interaction network construction, and analysis were performed. Moreover, small-molecule drug candidates have also been identified.
RESULTS
Three hundred and three upregulated and 59 downregulated genes were identified. Gene ontology function enrichment analyses were primarily related to inflammatory response, immune response, leukocyte migration, neutrophil chemotaxis, mitogen-activated protein kinase cascade, Jun N-terminal kinase cascade, I-kappaB kinase/nuclear factor-κB, and MyD88-dependent toll-like receptor signaling pathway. Pathway enrichment analyses and gene set enrichment analysis were mainly involved in cytokine-cytokine receptor interaction, the TNF signaling pathway, leukocyte transendothelial migration, and the NOD-like receptor signaling pathway. Furthermore, 1 important module and 10 hub genes (CXCL8, TLR2, CXCL1, ICAM1, CXCR4, FPR2, SELL, PTEN, TREM1, and LEP) were identified in the protein-protein interaction network. Moreover, indoprofen, mimosine, STOCK1N-35874, trapidil, iloprost, aminoglutethimide, ajmaline, levobunolol, ethionamide, cefaclor, dimenhydrinate, and bethanechol are potential drugs for the treatment of neutrophil-predominant severe asthma.
CONCLUSION
This study identified potential biomarkers, pathogenesis, and therapeutic molecular targets for neutrophil-predominant severe asthma.
Topics: Ajmaline; Aminoglutethimide; Asthma; Bethanechol; Biomarkers; Cefaclor; Computational Biology; Cytokines; Dimenhydrinate; Ethionamide; Gene Expression Profiling; Humans; Iloprost; Indoprofen; JNK Mitogen-Activated Protein Kinases; Levobunolol; Mimosine; Mitogen-Activated Protein Kinases; Myeloid Differentiation Factor 88; NF-kappa B; NLR Proteins; Neutrophils; Receptors, Cytokine; Toll-Like Receptor 2; Trapidil; Triggering Receptor Expressed on Myeloid Cells-1
PubMed: 36197221
DOI: 10.1097/MD.0000000000030661 -
Brain Research Oct 2021Brain penetration of cationic drugs is an important determinant of their efficacy and side effects. However, the effects of alterations in the activity of uptake...
Brain penetration of cationic drugs is an important determinant of their efficacy and side effects. However, the effects of alterations in the activity of uptake transporters in the brain under inflammatory conditions on the brain penetration of cationic drugs are not fully understood. The aim of this study was to examine changes in brain penetration of cationic drugs, including diphenhydramine (DPHM), memantine (MMT), and cimetidine (CMD), and changes in the expression of uptake transporters such as organic cation transporter (Oct) in brain microvascular endothelial cells (BMECs) under inflammatory conditions. To clarify the effects of inflammation on the brain penetration of DPHM, MMT, and CMD, we performed brain microdialysis studies in a rat model of adjuvant-induced arthritis (AA). Further, differences in transporter mRNA expression levels between BMECs from control and AA rats were evaluated. Brain microdialysis showed that the unbound brain-to-plasma partition coefficient (K) for DPHM and MMT was significantly lower in AA rats compared with control rats. OCT mRNA levels were increased and proton-coupled organic cation (H/OC) antiporter mRNA levels were decreased in AA rats compared with control rats. Taken together, our findings suggest that inflammation decreases the brain penetration of H/OC antiporter substrates such as DPHM and MMT.
Topics: Animals; Antiporters; Arthritis; Biological Transport; Blood-Brain Barrier; Brain; Cimetidine; Diphenhydramine; Endothelial Cells; Female; Inflammation; Memantine; Microdialysis; Rats; Rats, Sprague-Dawley
PubMed: 34280372
DOI: 10.1016/j.brainres.2021.147581 -
Postgraduate Medical Journal Feb 2017
Topics: Administration, Intravenous; Aged; Airway Management; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Bradykinin; Diphenhydramine; Endoscopy; Humans; Male; Methylprednisolone Hemisuccinate; Paresis; Tissue Plasminogen Activator; Tongue Diseases; Treatment Outcome
PubMed: 27888208
DOI: 10.1136/postgradmedj-2016-134501 -
Clinical Toxicology (Philadelphia, Pa.) Feb 2020Diphenhydramine (DPH) exposures in children may be the result of accidental unsupervised ingestions, caregiver error, and intentional misuse of DPH-containing cough and...
Diphenhydramine (DPH) exposures in children may be the result of accidental unsupervised ingestions, caregiver error, and intentional misuse of DPH-containing cough and cold medications (CCM). We sought to understand the nature of pediatric ingestions of DPH, particularly the toxicity and outcome of a single product, single ingredient DPH (DPH-only) exposures, in order to derive ingredient-specific information about the clinical effects and course of such cases. As part of a U.S. multi-year safety surveillance program to assess the safety of over-the-counter (OTC) medications used in cough and cold preparations in children <12 years of age, an expert panel reviewed cases involving symptomatic adverse events potentially related to oral exposures to these medications. After individual review, the cases were categorized by causal relationship of the reported ingredients to the adverse event, exposure intent (therapeutic, non-therapeutic, unknown intent), and dose (therapeutic, supratherapeutic, or unknown). Following panel review, any disagreement on classification was discussed until a consensus was reached. The data were then analyzed with respect to descriptive findings. The panel reviewed 6618 eligible cases and determined 2802 were at least potentially related to oral exposure to DPH. Of these, 2028 were DPH-only cases (39.1% of all cases judged at least potentially related to a cough and cold medication). The majority (79.5%) of DPH-only cases occurred in children 2 to <4 years of age and involved accidental unsupervised ingestions (74.7%). Liquid pediatric formulations were the most common (51.7%) products reported followed by solid pediatric formulations (24.0%). The most common adverse events were tachycardia (53.4%), hallucinations (46.5%), somnolence (34.7%), agitation (33.9%), and mydriasis (26.3%). Seizures occurred in only 5.5% of cases. Five (0.2%) deaths were reported; in the death cases, the DPH dose was judged supratherapeutic in one and unknown in the other four. Child abuse was reported in four of the five death cases and three of the five deaths were homicides. Exposures to DPH-only products were the most common type of exposure detected in our study of adverse events associated with CCM in children. The majority of the DPH-only cases were the result of accidental unsupervised ingestions. Most adverse events were relatively mild self-limited anticholinergic effects and few deaths occurred. Deaths involving DPH were often associated with child abuse or homicide. Interventions targeting the prevention of accidental unsupervised are likely to be impactful in preventing morbidity associated with DPH-only exposure.
Topics: Adverse Drug Reaction Reporting Systems; Antitussive Agents; Child; Cough; Diphenhydramine; Humans; Nonprescription Drugs
PubMed: 31062642
DOI: 10.1080/15563650.2019.1609683 -
Gastrointestinal Endoscopy Aug 2018Previous studies have described variable effects of fellow involvement on the adenoma detection rate (ADR), but few have stratified this effect by level of training. We...
BACKGROUND AND AIMS
Previous studies have described variable effects of fellow involvement on the adenoma detection rate (ADR), but few have stratified this effect by level of training. We aimed to evaluate the "fellow effect" on multiple procedural metrics including a newly defined adenoma management efficiency index, which may have a role in documenting colonoscopy proficiency for trainees. We also describe the impact of level of training on moderate sedation use.
METHODS
We performed a retrospective review of 2024 patients (mean age, 60.9 ± 10 years; 94% men) who underwent outpatient colonoscopy between June 2012 and December 2014 at our Veterans Affairs Medical Center. Colonoscopies were divided into 5 groups. The first 2 groups were first-year fellows in the first 6 months and last 6 months of the training year. Second- and third-year fellows and attending-only procedures accounted for 1 group each. We collected data on doses of sedatives used, frequency of adjunctive agent use, procedural times, and location, size, and histology of polyps. We defined the adenoma management efficiency index as average time required per adenoma resected during withdrawal.
RESULTS
Of the colonoscopies performed, 1675 involved a fellow and 349 were performed by the attending alone. There was no difference in ADR between fellows according to level of training (P = .8) or between fellows compared with attending-only procedures (P = .67). Procedural times decreased consistently during training and declined further for attending-only procedures. This translated into improvement in the adenoma management efficiency index (fellow groups by ascending level of training: 23.5 minutes vs 18.3 minutes vs 13.7 minutes vs 13.4 minutes vs attending group 11.7 minutes; P < .001). There was no difference in the average doses of midazolam and fentanyl used among fellow groups (P = .16 and P = .1, respectively). Compared with attending-only procedures, fellow involvement was associated with higher doses of fentanyl and midazolam and more frequent use of diphenhydramine and glucagon (P < .0001, P = .0002, P < .0001, and P = .01, respectively).
CONCLUSIONS
ADR was similar at different stages of fellowship training and comparable with the attending group. Efficiency of detecting and resecting polyps improved throughout training without reaching the attending level. Fellow involvement led to a greater use of moderate sedation, which may relate to a longer procedure duration and an evolving experience in endoscopic technique.
Topics: Adenoma; Adjuvants, Anesthesia; Aged; Clinical Competence; Colonic Polyps; Colonoscopy; Colorectal Neoplasms; Diphenhydramine; Fellowships and Scholarships; Female; Fentanyl; Gastroenterology; Gastrointestinal Agents; Glucagon; Humans; Hypnotics and Sedatives; Male; Medical Staff, Hospital; Midazolam; Middle Aged; Operative Time; Retrospective Studies
PubMed: 29679692
DOI: 10.1016/j.gie.2018.04.2338 -
Gastrointestinal Endoscopy Sep 2015Sedative and analgesic medications have been used routinely for decades to provide patient comfort, reduce procedure time, and improve examination quality during...
BACKGROUND
Sedative and analgesic medications have been used routinely for decades to provide patient comfort, reduce procedure time, and improve examination quality during colonoscopy.
OBJECTIVE
To evaluate trends of sedation during colonoscopy in the United States.
SETTING
Endoscopic data repository of U.S. gastroenterology practices (Clinical Outcomes Research Initiative, CORI database from 2000 until 2013).
PATIENTS
The study population was made up of patients undergoing a total of 1,385,436 colonoscopies.
INTERVENTIONS
Colonoscopy without any intervention or with mucosal biopsy, polypectomy, various means of hemostasis, luminal dilation, stent placement, or ablation.
MAIN OUTCOME MEASUREMENTS
Dose of midazolam, diazepam, fentanyl, meperidine, diphenhydramine, promethazine, and propofol used for sedation during colonoscopy.
RESULTS
During the past 14 years, midazolam, fentanyl, and propofol have become the most commonly used sedatives for colonoscopy. Except for benzodiazepines, which were dosed higher in women than men, equal doses of sedation were given to female and male patients. White patients were given higher doses than other ethnic groups undergoing sedation for colonoscopy. Except for histamine-1 receptor antagonists, all sedative medications were given at lower doses to patients with increasing age. The dose of sedatives was higher in colonoscopies associated with procedural interventions or of long duration.
LIMITATIONS
Potential for incomplete or incorrect documentation in the database.
CONCLUSION
The findings reflect on colonoscopy practice in the United States during the last 14 years and provide an incentive for future research on how sex and ethnicity influence sedation practices.
Topics: Adenoma; Adult; Black or African American; Aged; Aged, 80 and over; Analgesics, Opioid; Biopsy; Catheter Ablation; Cohort Studies; Colonic Polyps; Colonoscopy; Colorectal Neoplasms; Conscious Sedation; Databases, Factual; Diazepam; Dilatation; Diphenhydramine; Early Detection of Cancer; Female; Fentanyl; Hispanic or Latino; Humans; Hypnotics and Sedatives; Linear Models; Male; Meperidine; Midazolam; Middle Aged; Multivariate Analysis; Pain Management; Practice Patterns, Physicians'; Promethazine; Propofol; Retrospective Studies; Stents; White People; Young Adult
PubMed: 25851159
DOI: 10.1016/j.gie.2015.01.041