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Redox Biology Jul 2024Inflammation and subsequent mitochondrial dysfunction and cell death worsen outcomes after revascularization in ischemic stroke. Receptor-interacting protein kinase 1...
Modulation of NLRP3 inflammasome-related-inflammation via RIPK1/RIPK3-DRP1 or HIF-1α signaling by phenothiazine in hypothermic and normothermic neuroprotection after acute ischemic stroke.
BACKGROUND
Inflammation and subsequent mitochondrial dysfunction and cell death worsen outcomes after revascularization in ischemic stroke. Receptor-interacting protein kinase 1 (RIPK1) activated dynamin-related protein 1 (DRP1) in a NLRPyrin domain containing 3 (NLRP3) inflammasome-dependent fashion and Hypoxia-Inducible Factor (HIF)-1α play key roles in the process. This study determined how phenothiazine drugs (chlorpromazine and promethazine (C + P)) with the hypothermic and normothermic modality impacts the RIPK1/RIPK3-DRP1 and HIF-1α pathways in providing neuroprotection.
METHODS
A total of 150 adult male Sprague-Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. 8 mg/kg of C + P was administered at onset of reperfusion. Infarct volumes, mRNA and protein expressions of HIF-1α, RIPK1, RIPK3, DRP-1, NLRP3-inflammation and cytochrome c-apoptosis were assessed. Apoptotic cell death, infiltration of neutrophils and macrophages, and mitochondrial function were evaluated. Interaction between RIPK1/RIPK3 and HIF-1α/NLRP3 were determined. In SH-SY5Y cells subjected to oxygen/glucose deprivation (OGD), the normothermic effect of C + P on inflammation and apoptosis were examined.
RESULTS
C + P significantly reduced infarct volumes, mitochondrial dysfunction (ATP and ROS concentration, citrate synthase and ATPase activity), inflammation and apoptosis with and without induced hypothermia. Overexpression of RIPK1, RIPK3, DRP-1, NLRP3-inflammasome and cytochrome c-apoptosis were all significantly reduced by C + P at 33 °C and the RIPK1 inhibitor (Nec1s), suggesting hypothermic effect of C + P via RIPK1/RIPK3-DRP1pathway. When body temperature was maintained at 37 °C, C + P and HIF-1α inhibitor (YC-1) reduced HIF-1α expression, leading to reduction in mitochondrial dysfunction, NLRP3 inflammasome and cytochrome c-apoptosis, as well as the interaction of HIF-1α and NLRP3. These were also evidenced in vitro, indicating a normothermic effect of C + P via HIF-1α.
CONCLUSION
Hypothermic and normothermic neuroprotection of C + P involve different pathways. The normothermic effect was mediated by HIF-1α, while hypothermic effect was via RIPK1/RIPK3-DRP1 signaling. This provides a theoretical basis for future precise exploration of hypothermic and normothermic neuroprotection.
Topics: Animals; Receptor-Interacting Protein Serine-Threonine Kinases; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Ischemic Stroke; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Signal Transduction; Inflammasomes; Dynamins; Rats, Sprague-Dawley; Phenothiazines; Inflammation; Neuroprotection; Humans; Disease Models, Animal; Hypothermia, Induced
PubMed: 38692093
DOI: 10.1016/j.redox.2024.103169 -
International Journal of Surgery Case... Oct 2023Baclofen is a γ -aminobutyric acid (GABA) agonist used to treat spasticity; however, it may be toxic at dosages above 200 mg. The psychological, nervous,...
INTRODUCTION
Baclofen is a γ -aminobutyric acid (GABA) agonist used to treat spasticity; however, it may be toxic at dosages above 200 mg. The psychological, nervous, cardiovascular, gastrointestinal, musculoskeletal, and respiratory systems are all affected. This report represents a case with the rare respiratory complications brought on by baclofen toxicity: atelectasis and pneumomediastinum.
PRESENTATION OF CASE
A 19-year-old female was admitted to the emergency department after attempting suicide by taking 20 baclofen tablets (500 mg). Imaging revealed pneumomediastinum, atelectasis, and a leftward displacement of mediastinal structures. Her therapy included a chest tube to relieve the pneumomediastinum and sodium valproate, promethazine, biperiden, and quetiapine for neurological symptoms. Four days after being admitted, she was successfully extubated without any complications.
DISCUSSION
Baclofen activates GABA-A and GABA-B receptors. High doses of baclofen may induce central nervous system and respiratory depression, requiring intensive care. GABA receptors may cause hallucinations, delusions, and agitation in baclofen overdose. High dosages of baclofen may cause bronchial and bronchiolar muscular spasms, leading to breathing problems and atelectasis. Recent animal studies on baclofen toxicity showed that increased alveolar pressure, circulatory abnormalities, edema, alveolar hemorrhages, and infiltration cause rupture and pneumomediastinum. Pneumomediastinum may need bed rest, oxygen, antitussives, and analgesics, but severe cases may necessitate a chest tube.
CONCLUSION
A high index of suspicion is required for early diagnosis of acute baclofen poisoning, which could manifest as respiratory complications, including pneumomediastinum and atelectasis. Since most cases are benign, it is still crucial for clinicians to detect complications early for further management.
PubMed: 37801962
DOI: 10.1016/j.ijscr.2023.108901 -
European Clinical Respiratory Journal 2023Sedating antihistamines such as promethazine are used as anxiolytics and hypnotic agents for patients with chronic obstructive pulmonary disease (COPD) with and without...
BACKGROUND
Sedating antihistamines such as promethazine are used as anxiolytics and hypnotic agents for patients with chronic obstructive pulmonary disease (COPD) with and without asthma despite limited knowledge of its effects and side effects. We evaluated if treatment with promethazine had a lower risk of harmful outcome.
METHODS
Nationwide retrospective cohort study of Danish specialist diagnosed outpatients with COPD treated with promethazine or an active comparator (melatonin). Patients with collection of promethazine or melatonin were propensity score matched 1:1. The primary outcome was a composite of severe COPD exacerbations and death from all causes analyzed by Cox proportional hazards regression. We performed an interaction analysis for comorbid asthma.
RESULTS
In our registry of 56,523 patients with COPD, 5,661 collected promethazine ( = 3,723) or melatonin ( = 1,938). A cohort of 3,290 promethazine- or melatonin-treated patients matched 1:1 was available for the primary analysis.Within 1-year patients treated with promethazine were at higher risk of the primary outcome than matched controls with a Hazard Ratio (HR) of 1.42 (CI 1.27-1.58, < 0.0001). Similarly, the risk of death was higher for promethazine-treated patients (HR 1.53, CI 1.32-1.77, < 0.0001). An interaction analysis for comorbid asthma showed no interaction between comorbid asthma and the likelihood of a primary outcome when collecting promethazine ( = 0.19). Adjusted Cox analysis on the entire population indicated a further increased risk with more promethazine (HR for primary outcome among patients collecting ≥ 400 promethazine tablets/year=2.15, CI 1.94-2.38, <0.0001).
CONCLUSIONS
Promethazine-treated patients with COPD had a concerning excess risk of a composite outcome of severe exacerbations and death from all causes compared to melatonin.
PubMed: 37680536
DOI: 10.1080/20018525.2023.2250604 -
Effectiveness of promethazine on preoperative and intraoperative sequelae in cleft palate surgeries.Orthodontics & Craniofacial Research Jun 2024Anxiety and nosocomial infection are the most common reported problems in children undergoing cleft surgeries. Research shows that there is an enigma in the use of... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Anxiety and nosocomial infection are the most common reported problems in children undergoing cleft surgeries. Research shows that there is an enigma in the use of antihistamine therapy in children for the management of upper respiratory tract infection. 'Promethazine' is a first-generation H1 receptor antagonist, and antihistamine also has strong sedative effects. Our study aims at evaluating the Effectiveness of Promethazine (Phenergan) in preoperative and intra operative sequelae in cleft surgeries.
MATERIALS AND METHODS
This is a single-centre, parallel, randomized, double-blinded randomized control clinical trial, which was conducted among 128 children between 2 and 4 years of age undergoing cleft palate surgery under general anaesthesia. After randomization, the case group was subjected to promethazine syrup 1 mg/kg body weight twice a day, orally for 3 days. The primary outcomes were preoperative anxiety levels which were recorded by children fear scale. The secondary outcomes include preoperative sleep quality and cough rate of children which are recorded by using sleep and cough objective scale respectively. The intraoperative heart rate is monitored with an ECG connected to a monitor.
RESULTS
Promethazine causes a reduction in the anxiety level by 70%, 64% reduction in cold and cough, improvement in sleep score by 70% and the heart rate was found to be stable throughout the surgery when compared to the control group.
CONCLUSION
As the benefits of promethazine in cleft palate surgery rule over its adverse effects, promethazine is considered safe to be used as premedication for children undergoing cleft palate surgeries.
Topics: Humans; Promethazine; Cleft Palate; Child, Preschool; Male; Female; Double-Blind Method; Histamine H1 Antagonists; Anxiety; Preoperative Care; Treatment Outcome; Heart Rate; Preoperative Period
PubMed: 38265116
DOI: 10.1111/ocr.12743 -
Letters in Applied Microbiology Oct 2023This study evaluated the antibiofilm activity of promethazine, deferiprone, and Manuka honey against Staphylococcus aureus and Pseudomonas aeruginosa in vitro and ex...
This study evaluated the antibiofilm activity of promethazine, deferiprone, and Manuka honey against Staphylococcus aureus and Pseudomonas aeruginosa in vitro and ex vivo in a wound model on porcine skin. The minimum inhibitory concentrations (MICs) and the effects of the compounds on biofilms were evaluated. Then, counting colony-forming units (CFUs) and confocal microscopy were performed on biofilms cultivated on porcine skin for evaluation of the compounds. For promethazine, MICs ranging from 97.66 to 781.25 µg/ml and minimum biofilm eradication concentration (MBEC) values ranging from 195.31 to 1562.5 µg/ml were found. In addition to reducing the biomass of both species' biofilms. As for deferiprone, the MICs were 512 and >1024 µg/ml, the MBECs were ≥1024 µg/ml, and it reduced the biomass of biofilms. Manuka honey had MICs of 10%-40%, MBECs of 20 to >40% and reduced the biomass of S. aureus biofilms only. Concerning the analyses in the ex vivo model, the compounds reduced (P < .05) CFU counts for both bacterial species, altering the biofilm architecture. The action of the compounds on biofilms in in vitro and ex vivo tests raises the possibility of using them against biofilm-associated wounds. However, further studies are needed to characterize the mechanisms of action and their effectiveness on biofilms in vivo.
Topics: Animals; Swine; Staphylococcus aureus; Promethazine; Deferiprone; Honey; Biofilms; Pseudomonas aeruginosa; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 37791895
DOI: 10.1093/lambio/ovad119 -
Environmental Science and Pollution... Jul 2023This research aims to remove two phenothiazines, promazine (PRO) and promethazine (PMT), from their individual and binary mixtures using olive tree pruning biochar...
Competitive adsorptive removal of promazine and promethazine from wastewater using olive tree pruning biochar: operational parameters, kinetics, and equilibrium investigations.
This research aims to remove two phenothiazines, promazine (PRO) and promethazine (PMT), from their individual and binary mixtures using olive tree pruning biochar (BC-OTPR). The impact of individual and combinatory effects of operational variables was evaluated for the first time using central composite design (CCD). Simultaneous removal of both drugs was maximized utilizing the composite desirability function. At low concentrations, the uptake of PRO and PMT from their individual solutions was achieved with high efficiency of 98.64%, 47.20 mg/g and 95.87%, 38.16 mg/g, respectively. No major differences in the removal capacity were observed for the binary mixtures. Characterization of BC-OTPR confirmed successful adsorption and showed that the OTPR surface was predominantly mesoporous. Equilibrium investigations revealed that the Langmuir isotherm model best describes the sorption of PRO/PMT from their individual solutions with maximum adsorption capacities of 640.7 and 346.95 mg/g, respectively. The sorption of PRO/PMT conforms to the pseudo-second-order kinetic model. Regeneration of the adsorbent surface was successfully done with desorption efficiencies of 94.06% and 98.54% for PRO and PMT, respectively, for six cycles.
Topics: Wastewater; Promethazine; Olea; Promazine; Kinetics; Adsorption; Charcoal; Water Pollutants, Chemical; Hydrogen-Ion Concentration
PubMed: 37326738
DOI: 10.1007/s11356-023-27688-6 -
Frontiers in Neurology 2023One of the most prevalent types of epilepsy is temporal lobe epilepsy (TLE), which has unknown etiological factors and drug resistance. The detailed mechanisms...
One of the most prevalent types of epilepsy is temporal lobe epilepsy (TLE), which has unknown etiological factors and drug resistance. The detailed mechanisms underlying potassium channels in human TLE have not yet been elucidated. Hence, this study aimed to mine potassium channel genes linked to TLE using a bioinformatic approach. The results found that Four key TLE-related potassium channel genes (TERKPCGs) were identified: potassium voltage-gated channel subfamily E member () 1, , potassium inwardly rectifying channel, subfamily J, member 11 (), and . A protein-protein interaction (PPI) network was constructed to analyze the relationship between TERKPCGs and other key module genes. The results of gene set enrichment analysis (GSEA) for a single gene indicated that the four TERKPCGs were highly linked to the cation channel, potassium channel, respiratory chain, and oxidative phosphorylation. The mRNA-TF network was established using four mRNAs and 113 predicted transcription factors. A ceRNA network containing seven miRNAs, two mRNAs, and 244 lncRNAs was constructed based on the TERKPCGs. Three common small-molecule drugs (enflurane, promethazine, and miconazole) target , and . Ten small-molecule drugs (glimepiride, diazoxide, levosimendan, and thiamylal et al.) were retrieved for . Compared to normal mice, the expression of , , , and was downregulated in the brain tissue of the epilepsy mouse model at both the transcriptional and translational levels, which was consistent with the trend of human data from the public database. The results indicated that key potassium channel genes linked to TLE were identified based on bioinformatics analysis to investigate the potential significance of potassium channel genes in the development and treatment of TLE.
PubMed: 37483435
DOI: 10.3389/fneur.2023.1175007 -
Journal of Nepal Health Research Council Sep 2023Photosensitivity is the response of drug or drug product to the exposure of solar, UV and visible light in the solid, semisolid, or liquid state that leads to a physical...
BACKGROUND
Photosensitivity is the response of drug or drug product to the exposure of solar, UV and visible light in the solid, semisolid, or liquid state that leads to a physical or chemical change. Exposure to light is a concern with numerous medications due to the potential for photo degradation or other chemical reactions that affect drug stability.
METHODS
Out of all the registered brands in Department of Drug Administration, 9 brands of Rabeprazole tablets, 5 brands of Promethazine tablets and 5 brands of methylcobalamin tablets were selected and were subjected for testing and analysis for various quality parameters as per pharmacopoeia. The labels of the collected medicine were analyzed. The obtained data were entered and analyzed in Microsoft office excel 2019.
RESULTS
Eleven products did not comply with the existing regulatory requirement on labeling system of medicine as per Regulation of Standard of drugs. There was no uniformity in mentioning the self-life. Similarly, large variation was seen on price of same generic drugs. Information regarding storage conditions, direction for use and category of the drug were lacking in the label of some brands of medicines.Upon Laboratory analysis, two brands of promethazine tablets and three brands of Rabeprazole tablets were found substandard. Drug content of all the brands of Methylcobalamin was found to contain overage.
CONCLUSIONS
The result of this study indicates that substandard medicines are abundant in Nepalese market. There is weak regulation monitoring which have resulted in no uniformity in similar pharmaceutical products too. Hence, stringent regulatory monitoring is required to assessthe quality of pharmaceutical products in the Nepalese market.
PubMed: 37742143
DOI: 10.33314/jnhrc.v21i1.4131 -
The American Journal of Nursing Apr 2024
Topics: Humans; Promethazine
PubMed: 38511703
DOI: 10.1097/01.NAJ.0001010556.28403.79 -
Journal of Pharmaceutical and... Aug 2024The misuse of pharmaceuticals has significantly increased in recent decades, becoming a major public health concern. The risks associated with medication misuse are...
Milligram scale enantioresolution of promethazine and its main metabolites, determination of their absolute configuration and assessment of enantioselective effects on human SY-SY5Y cells.
The misuse of pharmaceuticals has significantly increased in recent decades, becoming a major public health concern. The risks associated with medication misuse are particularly high in cases of overdose, especially when the active substances are chiral, as enantioselectivity plays an important role in toxicity. Promethazine (PMZ) is a chiral antihistamine marketed as a racemate and it is misused in "Purple Drank", a recreational drug beverage, that combines codeine and/or PMZ, with soda or alcohol leading to serious health consequences and fatalities in consumers around the world, particularly among teenagers. Information regarding the enantioselectivity in the toxicity of (R,S)-PMZ and its main metabolites, namely promethazine sulfoxide (PMZSO) and desmonomethyl promethazine (DMPMZ), is unknown. This work reported, for the first time, the enantioseparation, in milligram scale, of (R,S)-PMZ, (R,S)-DMPMZ, (R,S)- PMZSO and the determination of their absolute configurations by electronic circular dichroism (ECD). The enantioseparation of all the six enantiomers was accomplished in a homemade semi-preparative column with amylose tris-3,5-dimethylphenylcarbamate (AD) coated with aminopropyl Nucleosil silica. The enantiomeric purity was evaluated using the analytical Lux® 3 µm i-Amylose-3 column, yielding enantiomeric purity values ranging between 94.4% and 99.7%. The elution order of all the enantiomers was accomplished combining the ECD results with an optical rotation detector. The elution order of the enantiomers was influenced only by the chiral selector, rather than the mobile phase. The cytotoxicity of the racemates and the isolated enantiomers towards differentiated SH-SY5Y cells was evaluated. (R,S)-DMPMZ exhibited a significantly higher cytotoxicity than (R,S)-PMZ, suggesting the metabolic bioactivation of (R,S)-PMZ. Conversely, no significant cytotoxicity was found for (R,S)-PMZSO, underscoring a metabolic detoxification pathway. Remarkably, enantioselectivity was observed for the cytotoxicity of PMZ; (R)-PMZ was significantly more cytotoxic than (S)-PMZ. The results underscore the importance to isolate the enantiomers in their enantiomerically form and their correct identification for toxicity enantioselectivity studies, which are vital to understand the drug's behaviour and safety, especially in case of overdoses.
Topics: Promethazine; Stereoisomerism; Humans; Cell Line, Tumor; Circular Dichroism; Cell Survival; Chromatography, High Pressure Liquid
PubMed: 38643704
DOI: 10.1016/j.jpba.2024.116152