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Frontiers in Pediatrics 2022Methylxanthines (caffeine; aminophylline/theophylline) are commonly used for apnea of prematurity (AOP) treatment. We aimed to compare the efficacy and adverse effects...
BACKGROUND
Methylxanthines (caffeine; aminophylline/theophylline) are commonly used for apnea of prematurity (AOP) treatment. We aimed to compare the efficacy and adverse effects of caffeine and aminophylline/theophylline.
METHODS
A retrospective case-control gestational age-matched study investigates patients born between January 2017 and December 2018, 23-35 weeks gestation with birth weights >500 g treating AOP with caffeine or aminophylline/theophylline.
RESULTS
There were 144 cases (48 in caffeine group and 96 in aminophylline/theophylline group). The median treatment durations were 11 and 17 days in caffeine and aminophylline/theophyllinegroup ( = 0.002). When tachycardia is defined as heart rate ≥160 bpm, the rates were 8.3 and 34.4% in caffeine and control group ( = 0.001). When tachycardia is defined as 10 bpm over baseline heart rate, the rates were 41.7 and 63.5% in caffeine and aminophylline/theophylline group ( = 0.01). Stratified by gestational age and sex, significant reductions in tachycardia rates with caffeine than with theophylline were limited to male infants and infants born at <30 weeks gestation.
CONCLUSIONS
For apnea treatment, caffeine has greater efficacy and fewer tachycardia than aminophylline/theophylline, especially in male infants and infants born at <30 weeks gestation.
PubMed: 35281246
DOI: 10.3389/fped.2022.817624 -
Annals of Translational Medicine Feb 2022Aminophylline is widely used for the treatment of asthma, but the therapeutic dose is very close to the toxic dose, which makes this drug prone to accumulation...
BACKGROUND
Aminophylline is widely used for the treatment of asthma, but the therapeutic dose is very close to the toxic dose, which makes this drug prone to accumulation poisoning. In the present study, we explored whether the Chinese herbal component, Praeruptorin E (PE), enhances anti-asthma efficacy and prevents the toxicity of aminophylline.
METHODS
First, an ovalbumin (OVA)-induced mouse model of asthma, immunohistochemistry, pathological staining, and bronchoalveolar lavage fluid (BALF) were used to detect the lung condition of asthmatic mice. The content of Th2 cytokines in serum was measured by enzyme-linked immunosorbent assay (ELISA), and the expression of related proteins was detected by Western blotting and immunofluorescence. Concentrations of theophylline and its metabolites in rat serum were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). siRNA transfection and chromatin immunoprecipitation (ChIP) were used to investigate the mechanism of PE.
RESULTS
PE was found to synergize with aminophylline to reduce the infiltration of inflammatory cells, collagen deposition, and mucus hyperplasia in the lungs of asthmatic mice. It inhibited the expression of Th2 cytokines, interleukin (IL)-4, IL-5, and IL-13; promoted lung tissue repair; and reduced the toxic effect of aminophylline on the heart. Moreover, LC-MS/MS analysis showed that PE reduced the plasma concentration of the parent theophylline and its metabolite 1,3-dimethyluric acid (1,3-DMU). PE facilitated aminophylline's suppression of nuclear factor-κB (), and increased the expression of the xenobiotic nuclear receptor pregnane X receptor () and its primary target gene, [this is the mouse homolog of cytochrome P450 3A ()] in the asthmatic mouse liver and in the L-02 human fetal hepatocyte cell culture model. In addition, the ChIP assay revealed that PE attenuated the binding of to the promoter region of the PXR gene and prevented the suppression of gene expression by .
CONCLUSIONS
PE has a dual function in enhancing the immune regulation and anti-inflammatory effects of theophylline, as well as preventing theophylline toxicity by targeting the NF-κB/PXR/CYP3A4 axis. PE is a promising herbal medicine that will benefit asthmatics taking theophylline.
PubMed: 35280431
DOI: 10.21037/atm-22-386 -
Journal of Ethnopharmacology May 2022The species Lippia origanoides Kunth, popularly known as "salva-de-marajó", is used in Brazilian traditional "quilombola" communities to treat menstrual cramps and...
ETHNOPHARMACOLOGICAL RELEVANCE
The species Lippia origanoides Kunth, popularly known as "salva-de-marajó", is used in Brazilian traditional "quilombola" communities to treat menstrual cramps and uterine inflammation.
AIM OF THE STUDY
Evaluate the spasmolytic activity of Lippia origanoides essential oil (LOO) on experimental models of uterine conditions related to menstrual cramps and investigate its mechanism of action.
MATERIALS AND METHODS
Virgin rat-isolated uterus was mounted in the organ bath apparatus to evaluate the spasmolytic effect of LOO on basal tonus and contractions induced by carbachol, KCl, or oxytocin. We used pharmacological agents to verify the relaxation mechanism of LOO. The evaluation of uterine contractility in virgin rats, after treatment with LOO for three consecutive days, was carried out by the construction of a concentration-response curve with oxytocin or carbachol. The primary dysmenorrhea animal model was replicated with an injection of estradiol cypionate in female mice for three consecutive days, followed by intraperitoneal application of oxytocin.
RESULTS
LOO relaxed the rat uterus precontracted with 10 IU/mL oxytocin (logEC = 1.98 ± 0.07), 1 μM carbachol (logEC = 1.42 ± 0.07) or 60 mM KCl (logEC = 1.53 ± 0.05). It was also able relax uterus on spontaneous contractions (logEC = 0.41 ± 0.05). Preincubation with glibenclamide, propranolol, phentolamine or L-NAME in contractions induced by carbachol did not alter significantly the relaxing effect of LOO. However, in the presence of 4-aminopyridine, CsCl or tetraethylammonium there was a reduction of LOO potency, whereas the blockers methylene blue, ODQ, aminophylline and heparin potentiated the LOO relaxing effect. Preincubation with LOO in a Ca free medium at concentrations of 27 μg/mL or 81 μg/mL reduced the contraction induced by carbachol. The administration of LOO for 3 days did not alter uterus contractility. The treatment with LOO at 30 or 100 mg/kg intraperitoneally, or 100 mg/kg orally, inhibited writhing in female mice. The association of LOO at 10 mg/kg with nifedipine or mefenamic acid potentiated writhing inhibition in mice.
CONCLUSIONS
The essential oil of L. origanoides has tocolytic activity in rat isolated uterus pre-contracted with KCl, oxytocin, or carbachol. This effect is possibly related to the opening of potassium channels (K, K and K), cAMP increase, and diminution of intracellular Ca. This relaxant effect, probably, contributed to reduce the number of writhings in an animal model of dysmenorrhea being potentiated by nifedipine or mefenamic acid. Taken together, the results here presented indicate that this species has a pharmacological potential for the treatment of primary dysmenorrhea, supporting its use in folk medicine.
Topics: Animals; Calcium; Carbachol; Cyclic AMP; Dysmenorrhea; Female; Lippia; Mefenamic Acid; Muscle Contraction; Nifedipine; Oils, Volatile; Oxytocin; Potassium Channels; Potassium Chloride; Rats; Tocolytic Agents; Uterine Contraction; Uterus
PubMed: 35167934
DOI: 10.1016/j.jep.2022.115099 -
Alterations in the gut microbiome and metabolome profiles of septic rats treated with aminophylline.Journal of Translational Medicine Feb 2022The treatment of sepsis remains a major challenge worldwide. Aminophylline has been shown to have anti-inflammatory effects; however, the role of aminophylline in...
The treatment of sepsis remains a major challenge worldwide. Aminophylline has been shown to have anti-inflammatory effects; however, the role of aminophylline in sepsis, a disease characterized by immune dysregulation, is unknown. In this study, we combined microbiome sequencing and metabolomic assays to investigate the effect of aminophylline administration on the intestinal flora and metabolites in septic rats. Sixty SD rats were randomly divided into three groups: a sham-operated (SC) group, a sepsis model (CLP) group and a CLP + aminophylline treatment (Amino) group. The intestinal flora and metabolic profile of rats in the CLP group were significantly different than those of the SC group, while aminophylline administration resulted in a return to a state similar to healthy rats. Differential abundance analysis showed that aminophylline significantly back-regulated the abundance of Firmicutes, unidentified_Bacteria, Proteobacteria, Lactobacillus, Escherichia-Shigella and other dominant bacteria (P < 0.05) and altered chenodeoxycholic acid, isolithocholic acid and a total of 26 metabolites (variable importance in the projection (VIP) > 1, P < 0.05). In addition, we found that there were significant correlations between differential metabolites and bacterial genera of the Amino and CLP groups. For example, Escherichia-Shigella was associated with 12 metabolites, and Lactobacillus was associated with two metabolites (P < 0.05), suggesting that differences in the metabolic profiles caused by aminophylline were partly dependent on its influence on the gutmicrobiome. In conclusion, this study identified a novel protective mechanism whereby aminophylline could regulate disordered intestinal flora and metabolites in septic rats.
Topics: Aminophylline; Animals; Gastrointestinal Microbiome; Metabolome; Rats; Rats, Sprague-Dawley; Sepsis
PubMed: 35115021
DOI: 10.1186/s12967-022-03280-3 -
Frontiers in Pharmacology 2021Cardiac side effects of some pulmonary drugs are observed in clinical practice. Aminophylline, a methylxanthine bronchodilator with documented proarrhythmic action, may...
Cardiac side effects of some pulmonary drugs are observed in clinical practice. Aminophylline, a methylxanthine bronchodilator with documented proarrhythmic action, may serve as an example. Data on the action of aminophylline on cardiac cell electrophysiology and contractility are not available. Hence, this study was focused on the analysis of changes in the beat rate and contraction force of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and HL-1 cardiomyocytes in the presence of increasing concentrations of aminophylline (10 µM-10 mM in hPSC-CM and 8-512 µM in HL-1 cardiomyocytes). Basic biomedical parameters, namely, the beat rate (BR) and contraction force, were assessed in hPSC-CMs using an atomic force microscope (AFM). The beat rate changes under aminophylline were also examined on the HL-1 cardiac muscle cell line via a multielectrode array (MEA). Additionally, calcium imaging was used to evaluate the effect of aminophylline on intracellular Ca dynamics in HL-1 cardiomyocytes. The BR was significantly increased after the application of aminophylline both in hPSC-CMs (with 10 mM aminophylline) and in HL-1 cardiomyocytes (with 256 and 512 µM aminophylline) in comparison with controls. A significant increase in the contraction force was also observed in hPSC-CMs with 10 µM aminophylline (a similar trend was visible at higher concentrations as well). We demonstrated that all aminophylline concentrations significantly increased the frequency of rhythm irregularities (extreme interbeat intervals) both in hPSC-CMs and HL-1 cells. The occurrence of the calcium sparks in HL-1 cardiomyocytes was significantly increased with the presence of 512 µM aminophylline. We conclude that the observed aberrant cardiomyocyte response to aminophylline suggests an arrhythmogenic potential of the drug. The acquired data represent a missing link between the arrhythmic events related to the aminophylline/theophylline treatment in clinical practice and describe cellular mechanisms of methylxanthine arrhythmogenesis. An AFM combined with hPSC-CMs may serve as a robust platform for direct drug effect screening.
PubMed: 35111056
DOI: 10.3389/fphar.2021.789730 -
Anesthesiology and Pain Medicine Oct 2021Post-dural Puncture Headache (PDPH) is prevalent among individuals undergoing lumbar punctures. The non-invasive effect of some drugs, such as aminophylline on PDPH has...
OBJECTIVES
Post-dural Puncture Headache (PDPH) is prevalent among individuals undergoing lumbar punctures. The non-invasive effect of some drugs, such as aminophylline on PDPH has been investigated in several clinical studies. As there is no comprehensive systematic review and meta-analysis about the preventive and therapeutic effects of aminophylline on PDPH in the literature, the clinical effectiveness of this drug on the prevention and/or treatment of PDPH will be assessed in this study.
METHODS
PubMed/MEDLINE, Embase, WoS (Clarivate Analytics), the Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL Complete, Scopus, and Google Scholar as electronic databases will be precisely searched for clinical studies that assessed the effect of aminophylline on PDPH. Studies between 01-01-1980 and 30-06-2020 will be evaluated in this study, and there will not be any language restrictions. Contradictions between the reviewers within any phase of the study (screening, selecting, quality assessment, and data extraction) will be resolved by consensus; in case of unsolved disagreements, a third reviewer will eventually decide. The combination method will be applied according to the methodological resemblance in the selected articles using the Random Effect Model or the Fixed Effect Model. Also, for the included articles, forest plots will be drawn. For assessing statistical heterogeneity, the I statistic and the Q-statistic test will be applied. In addition, funnel plots will be used for assessing non-significant study effects and potential reporting bias. Furthermore, Egger's and Begg's tests will be done, and publication bias will be indicated by significant findings (P < 0.05).
CONCLUSIONS
It is expected that the results of this study will be of benefit to researchers and clinicians for managing PDPH, and will be reported in conferences and publications.
PubMed: 35075418
DOI: 10.5812/aapm.119674 -
Journal of Ethnopharmacology May 2022The Bu-Fei formula (BFF) has a positive effect on chronic obstructive pulmonary disease (COPD). However, its therapeutic mechanisms against COPD remain unknown.
ETHNOPHARMACOLOGICAL RELEVANCE
The Bu-Fei formula (BFF) has a positive effect on chronic obstructive pulmonary disease (COPD). However, its therapeutic mechanisms against COPD remain unknown.
AIM OF THE STUDY
To explore BFF's therapeutic effect on COPD and pharmacological mechanisms.
MATERIALS AND METHODS
First, the effect of BFF on rats with COPD was studied. Rats were randomly assigned to the blank, COPD, BFF treatment, and aminophylline (APL) treatment groups. From weeks 1-8, the COPD model was established by Klebsiella pneumoniae (KP) and cigarette smoke. Then, rats were given corresponding treatment for 8 weeks. The lung function of the rats was analyzed by whole-body plethysmography and pulmonary function testing, lung histopathology by electron microscopy and hematoxylin and eosin staining, and protein levels by immunohistochemistry. Next, the key components and targets of BFF in COPD were screened by network pharmacology analysis. Finally, the possible mechanism was verified through molecular docking and in vivo experiments.
RESULTS
BFF significantly improved lung function and lung histopathology in COPD rats and inhibit inflammation and collagen deposition in lung tissues. Also, 46 bioactive compounds and 136 BFF targets related to COPD were identified; among them, 3 compounds (quercetin, luteolin, and nobiletin) and 6 core targets (Akt1, BCL2, NF-κB p65, VEGFA, MMP9, and Caspase 8) were the key molecules associated with the mechanisms of BFF. The target enrichment analysis suggested that BFF's mechanisms might involve the apoptosis-related pathway; this possibility was supported by the molecular docking data. Lastly, BFF was indicated to increase the expression of core target genes and the production of apoptosis-related proteins.
CONCLUSIONS
BFF affects COPD by regulating the apoptosis-related pathways and targets.
Topics: Animals; Apoptosis; Collagen; Disease Models, Animal; Drugs, Chinese Herbal; Inflammation; Network Pharmacology; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Respiratory Function Tests
PubMed: 35074456
DOI: 10.1016/j.jep.2022.115022 -
Biomedicines Jan 2022Asthma is a common and heterogeneous disease characterized by chronic airway inflammation. Currently, the two main types of asthma medicines are inhaled corticosteroids...
Asthma is a common and heterogeneous disease characterized by chronic airway inflammation. Currently, the two main types of asthma medicines are inhaled corticosteroids and long-acting β2-adrenoceptor agonists (LABAs). In addition, biological drugs provide another therapeutic option, especially for patients with severe asthma. However, these drugs were less effective in preventing severe asthma exacerbation, and other drug options are still limited. Herein, we extracted asthma-associated single nucleotide polymorphisms (SNPs) from the genome-wide association studies (GWAS) and phenome-wide association studies (PheWAS) catalog and prioritized candidate genes through five functional annotations. Genes enriched in more than two categories were defined as "biological asthma risk genes." Then, DrugBank was used to match target genes with FDA-approved medications and identify candidate drugs for asthma. We discovered 139 biological asthma risk genes and identified 64 drugs targeting 22 of these genes. Seven of them were approved for asthma, including reslizumab, mepolizumab, theophylline, dyphylline, aminophylline, oxtriphylline, and enprofylline. We also found 17 drugs with clinical or preclinical evidence in treating asthma. In addition, eleven of the 40 candidate drugs were further identified as promising asthma therapy. Noteworthy, is considered a target for asthma drug repurposing based on its high target scores. Through in silico drug repurposing approach, we identified sarilumab and satralizumab as the most promising drug for asthma treatment.
PubMed: 35052792
DOI: 10.3390/biomedicines10010113 -
PloS One 2022Theophylline is an important drug for treatment of canine chronic bronchitis and bradyarrhythmias, but new products require validation since pharmacokinetics in dogs can...
Theophylline is an important drug for treatment of canine chronic bronchitis and bradyarrhythmias, but new products require validation since pharmacokinetics in dogs can vary by formulation. A new, 503B outsourcing facility-produced theophylline product (OFT) is available for veterinary use. Outsourcing facilities have many advantages over traditional compounding sources including current good manufacturing practice compliance. The purpose of this study was to establish the pharmacokinetics of OFT in dogs. Eight healthy dogs received 11 mg/kg intravenous aminophylline and 10 mg/kg oral OFT followed by serial blood sampling in a two-way, randomized, crossover design with 7-day washout. Plasma theophylline concentrations were quantified by liquid chromatography-mass spectrometry. Bioavailability, maximum concentration, time to maximum concentration, half-life and area under the curve were: 97 ± 10%, 7.13 ± 0.71 μg/mL, 10.50 ± 2.07 h, 9.20 ± 2.87 h, and 141 ± 37.6 μg*h/mL, respectively. Steady-state predictions supported twice daily dosing of the OFT, but specific dosage recommendations are hindered by lack of a canine-specific therapeutic range for plasma theophylline concentration. These findings suggest that the OFT is well absorbed and can likely be dosed twice daily in dogs, but future pharmacodynamic and clinical studies are needed to establish a definitive therapeutic range for theophylline in this species.
Topics: Aminophylline; Animals; Biological Availability; Bradycardia; Bronchitis, Chronic; Cross-Over Studies; Dogs; Female; Half-Life; Injections, Intravenous; Male; Outsourced Services; Theophylline
PubMed: 34990472
DOI: 10.1371/journal.pone.0262336 -
Brazilian Journal of Anesthesiology... 2022
Randomized Controlled Trial
Topics: Aminophylline; Anesthesia, Obstetrical; Anesthesia, Spinal; Cesarean Section; Dexamethasone; Female; Headache; Humans; Pregnancy
PubMed: 34933037
DOI: 10.1016/j.bjane.2021.11.012