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Journal of Thoracic Disease May 2024Theophylline has been used for decades in human medicine for its psychostimulant, anti-inflammatory, and bronchodilator effects. Historically, in pulmonary medicine,... (Review)
Review
BACKGROUND AND OBJECTIVE
Theophylline has been used for decades in human medicine for its psychostimulant, anti-inflammatory, and bronchodilator effects. Historically, in pulmonary medicine, theophylline has been used in the treatment of obstructive pulmonary diseases such as bronchial asthma (BA) or chronic obstructive pulmonary disease (COPD). This review aims to determine whether theophylline still has its place in the therapy of obstructive pulmonary diseases or whether we can even extend its use to other diagnoses such as atropine-resistant cardiac arrests, apnea of prematurity, or others. Moreover, we also aim to determine if there is a rationale for using low-dose theophylline due to its immunomodulatory and anti-inflammatory effect, or if the future of methylxanthines lies in newly synthesized derivates of theophylline such as bamifylline, or doxofylline.
METHODS
The narrative review is based on a literature search of the articles indexed in the PubMed database in 2023. We searched the database since the year 2009 using the MeSH terms "theophylline", "aminophylline", and "methylxanthines" and we included original articles in the English language.
KEY CONTENT AND FINDINGS
Theophylline has a number of adverse drug reactions (ADRs), the most serious of which is its effect on the cardiovascular system. It can cause severe arrhythmias or even cardiac arrest when overdosed. On the other hand, there is still a substantial amount of its applications in current clinical practice.
CONCLUSIONS
There is considerable controversy associated with its use in current medicine, which can be attributed both to its narrow therapeutic range and its mentioned cardiotoxic effect. Herein, we summarize the current state-of-art of theophylline and its use in human medicine.
PubMed: 38883616
DOI: 10.21037/jtd-23-1781 -
Acta Biochimica Et Biophysica Sinica May 2024Chronic renal failure (CRF) is a severe syndrome affecting the urinary system for which there are no effective therapeutics. In this study, we investigate the effects...
Chronic renal failure (CRF) is a severe syndrome affecting the urinary system for which there are no effective therapeutics. In this study, we investigate the effects and mechanisms of aminophylline in preventing CRF development. A rat model of chronic renal failure is established by 5/6 nephrectomy. The levels of serum creatinine (SCR), urinary protein (UPR), and blood urea nitrogen (BUN) are detected by ELISA. Histological evaluations of renal tissues are performed by H&E, Masson staining, and PAS staining. Functional protein expression is detected by western blot analysis or immunofluorescence microscopy. Glomerular cell apoptosis is determined using the TUNEL method. Results show that Aminophylline significantly reduces the levels of SCR, UPR, and BUN in the CRF model rats. Histological analyses show that aminophylline effectively alleviates renal tissue injuries in CRF rats. The protein expression levels of nephrin, podocin, SIRT1, p-AMPK, and p-ULK1 are greatly increased, while p-mTOR protein expression is markedly decreased by aminophylline treatment. Additionally, the protein level of LC3B in CRF rats is significantly increased by aminophylline. Moreover, aminophylline alleviates apoptosis in the glomerular tissues of CRF rats. Furthermore, resveratrol promotes SIRT1, p-AMPK, and p-ULK1 protein expressions and reduces p-mTOR and LC3B protein expressions in CRF rats. Selisistat (a SIRT1 inhibitor) mitigates the changes in SIRT1, p-AMPK, p-ULK1, p-mTOR, and LC3B expressions induced by aminophylline. Finally, RAPA alleviates renal injury and apoptosis in CRF rats, and 3-MA eliminates the aminophylline-induced inhibition of renal injury and apoptosis in CRF rats. Aminophylline suppresses chronic renal failure progression by modulating the SIRT1/AMPK/mTOR-mediated autophagy process.
PubMed: 38808395
DOI: 10.3724/abbs.2024049 -
International Journal of Molecular... May 2024Parkinson's disease (PD) is a progressive disorder characterized by the apoptosis of dopaminergic neurons in the basal ganglia. This study explored the potential effects...
Parkinson's disease (PD) is a progressive disorder characterized by the apoptosis of dopaminergic neurons in the basal ganglia. This study explored the potential effects of aminophylline, a non-selective adenosine A and A receptor antagonist, on catalepsy and gait in a haloperidol-induced PD model. Sixty adult male Swiss mice were surgically implanted with guide cannulas that targeted the basal ganglia. After seven days, the mice received intraperitoneal injections of either haloperidol (experimental group, PD-induced model) or saline solution (control group, non-PD-induced model), followed by intracerebral infusions of aminophylline. The assessments included catalepsy testing on the bar and gait analysis using the Open Field Maze. A two-way repeated-measures analysis of variance (ANOVA), followed by Tukey's post hoc tests, was employed to evaluate the impact of groups (experimental × control), aminophylline (60 nM × 120 nM × saline/placebo), and interactions. Significance was set at 5%. The results revealed that the systemic administration of haloperidol in the experimental group increased catalepsy and dysfunction of gait that paralleled the observations in PD. Co-treatment with aminophylline at 60 nM and 120 nM reversed catalepsy in the experimental group but did not restore the normal gait pattern of the animals. In the non-PD induced group, which did not present any signs of catalepsy or motor dysfunctions, the intracerebral dose of aminophylline did not exert any interference on reaction time for catalepsy but increased walking distance in the Open Field Maze. Considering the results, this study highlights important adenosine interactions in the basal ganglia of animals with and without signs comparable to those of PD. These findings offer valuable insights into the neurobiology of PD and emphasize the importance of exploring novel therapeutic strategies to improve patient's catalepsy and gait.
Topics: Animals; Catalepsy; Mice; Male; Aminophylline; Disease Models, Animal; Gait; Haloperidol; Parkinson Disease
PubMed: 38791229
DOI: 10.3390/ijms25105191 -
Novel Gene Mutation c.118G>A Causing Keratinocyte and Cardiomyocyte Disconnection in Darier Disease.Biomedicines May 2024Darier disease (DD) is an autosomal dominant disorder due to pathogenic variants of the gene that causes an isolated skin manifestation based on keratinocyte...
Darier disease (DD) is an autosomal dominant disorder due to pathogenic variants of the gene that causes an isolated skin manifestation based on keratinocyte disconnection and apoptosis. Systemic manifestations of DD have not been demonstrated so far, although a high incidence of neuropsychiatric syndromes suggests an involvement of the central nervous system. We report that the pathogenic ATP2A2 gene variant c.118G>A may cause cardiac involvement in patients with DD, consisting of keratinocyte and cardiomyocyte disconnection. Their common pathologic pathway, still unreported, was documented by both skin and left ventricular endomyocardial biopsies because cardiac dilatation and dysfunction appeared several decades after skin manifestations. Keratinocyte disconnection was paralleled by cardiomyocyte separation at the lateral junction. Cardiomyocyte separation was associated with cell disarray, sarcoplasmic reticulum dilatation, and increased myocyte apoptosis. Clinically, hyperkeratotic skin papules are associated with chest pain, severe muscle exhaustion, and ventricular arrhythmias that improved following administration of aminophylline, a phosphodiesterase inhibitor enhancing SERCA2 protein phosphorylation. Cardiac pathologic changes are similar to those documented in the skin, including cardiomyocyte disconnection that promotes precordial pain and cardiac arrhythmias. Phosphodiesterase inhibitors that enhance SERCA2 protein phosphorylation may substantially attenuate the symptoms.
PubMed: 38791022
DOI: 10.3390/biomedicines12051060 -
Anesthesiology and Pain Medicine Dec 2023The sympatholytic property of dexmedetomidine (DEX) makes it suitable as a hypotensive drug during functional endoscopic sinus surgery (FESS); however, delayed emergence...
Effect of Intravenous Aminophylline on Hemodynamics and Recovery of Patients Undergoing Functional Endoscopic Sinus Surgery Under Dexmedetomidine Hypotensive Anesthesia: A Randomized Controlled Study.
BACKGROUND
The sympatholytic property of dexmedetomidine (DEX) makes it suitable as a hypotensive drug during functional endoscopic sinus surgery (FESS); however, delayed emergence from anesthesia and high postoperative sedation have been reported.
OBJECTIVES
Delayed emergence from anesthesia and high postoperative sedation are associated with a prolonged length of stay in the operating room and the postanesthesia care unit (PACU), which increases health care costs. This study aimed to overcome the negative impact of DEX on recovery by using aminophylline.
METHODS
This randomized, double-blind, placebo-controlled study was conducted on 52 patients planned for elective FESS under general anesthesia with DEX infusion for controlled hypotension during surgery. Patients were equally divided into 2 groups. The aminophylline group received 4 mg/kg aminophylline diluted in 50 mL saline 0.9% over 30 minutes after positioning in a 20-degree reverse Trendelenburg position. The control group received 50 mL saline 0.9% with a similar volume and period as the aminophylline group.
RESULTS
The extubation time was significantly shorter in the aminophylline group (6.5 (5.25 - 7.75) minutes) than in the control group (9 (7.25 - 10) minutes) (P-value < 0.001). The PACU discharge time was significantly shorter in the aminophylline group (15 (10 - 20) minutes) compared to the control group (20 (15 - 28.75) minutes) (P-value = 0.036). Intraoperative heart rate and mean arterial pressure were nonsignificantly different between the 2 groups. Ramsay sedation score measurements at 15 min, 30 min, and 60 min after extubation were significantly lower in the aminophylline than in the control group (P-value < 0.05). Complications were nonsignificantly different between the 2 groups.
CONCLUSIONS
Intraoperative aminophylline infusion enhances the recovery of patients undergoing FESS under DEX hypotensive anesthesia without intraoperative hemodynamic alterations and decreases their postoperative sedation without significant postoperative side effects.
PubMed: 38721439
DOI: 10.5812/aapm-141669 -
Discovery Medicine Apr 2024The usage of life-saving mechanical ventilation (MV) could cause ventilator-induced diaphragmatic dysfunction (VIDD), increasing both mortality and morbidity....
BACKGROUND
The usage of life-saving mechanical ventilation (MV) could cause ventilator-induced diaphragmatic dysfunction (VIDD), increasing both mortality and morbidity. Aminophylline (AP) has the potential to enhance the contractility of animal skeletal muscle fibers and improve the activity of human respiratory muscles, and the insulin-like growth factor-1 (IGF-1)- forkhead box protein O1 (FOXO1)-muscle RING finger-1 (MURF1) pathway plays a crucial role in skeletal muscle dysfunction. This study aimed to investigate the impact of AP on VIDD and to elucidate the role of the IGF-1-FOXO1-MURF1 pathway as an underlying mechanism.
METHODS
Rat models of VIDD were established through MV treatment. lentiviral (LV) interference (LV--shRNA; controlled by lentiviral negative control LV-NC) was employed to inhibit expression and thereby block the IGF-1-FOXO1-MURF1 pathway. Protein and mRNA levels of , , and were assessed using western blot and real-time reverse transcriptase-polymerase chain reaction (RT-qPCR), respectively. Diaphragm contractility and morphometry were examined through measurement of compound muscle action potentials (CMAPs) and hematoxylin and eosin (H&E) staining. Oxidative stress was evaluated by levels of hydrogen peroxide (HO), superoxide dismutase (SOD), antioxidant glutathione (GSH), and carbonylated protein. Mitochondrial stability was assessed by measuring the mitochondrial membrane potential (MMP), and mitochondrial fission and mitophagy were examined through protein levels of dynamin-related protein 1 (DRP1), mitofusin 2 protein (MFN2), phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), and Parkin (western blot). Apoptosis was evaluated using the terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate (UTP) nick-end labeling (TUNEL) assay and levels of Bax, B-cell lymphoma 2 (), and Caspase-3. Levels of Atrogin-1, neuronally expressed developmentally downregulated 4 (), and muscle ubiquitin ligase of SCF complex in atrophy-1 () mRNA, as well as ubiquitinated protein, were utilized to determine protein degradation. Furthermore, the SUnSET (surface sensing of translation) method was employed to determine rates of protein synthesis.
RESULTS
MV treatment upregulated while downregulated and ( < 0.05). AP administration reversed , and ( < 0.05), which was suppressed again by inhibition ( < 0.05), demonstrating the blockage of the IGF-1-FOXO1-MURF1 pathway. MV treatment caused decreased CMAP and cross-sectional areas of diaphragm muscle fibers, and increased time course of CMAP ( < 0.05). Additionally, oxidative stress, cell apoptosis, and protein degradation were increased and mitochondrial stability was decreased by MV treatment ( < 0.05). Conversely, AP administration reversed all these changes induced by MV, but this reversal was disrupted by the blockage of the IGF-1-FOXO1-MURF1 pathway.
CONCLUSIONS
In this study, MV treatment induced symptoms of VIDD in rats, which were all effectively reversed by AP regulating the IGF-1-FOXO1-MURF1 pathway, demonstrating the potential of AP in ameliorating VIDD.
Topics: Animals; Male; Rats; Aminophylline; Diaphragm; Forkhead Box Protein O1; Insulin-Like Growth Factor I; Muscle Proteins; Oxidative Stress; Rats, Sprague-Dawley; Respiration, Artificial; Signal Transduction; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 38665019
DOI: 10.24976/Discov.Med.202436183.66 -
Alternative Therapies in Health and... Apr 2024To study and compare the efficacy and clinical value of aminophylline and doxofylline in the clinical treatment of chronic obstructive pulmonary disease (COPD).
OBJECTIVE
To study and compare the efficacy and clinical value of aminophylline and doxofylline in the clinical treatment of chronic obstructive pulmonary disease (COPD).
METHOD
The study analyzed the clinical data of 92 patients with chronic obstructive pulmonary disease who received either aminophylline or doxofylline treatment in the hospital from January 2020 to June 2022. The patients were divided into a control group composed of 46 COPD patients who received aminophylline treatment and a study group composed of 46 COPD patients who received doxofylline treatment. The two groups' total effective rate and incidence of adverse reactions were compared. The serum inflammatory factor indicators, symptom scores, pulmonary ventilation function, arterial blood gas, chest and lung responsiveness, sleep status indicators, and quality of life scores of the two groups before and after treatment were compared.
RESULTS
At the end of treatment, the total effective rate was higher in the study group compared to the control group (P < .05). Regarding adverse reactions, the study group's total incidence was lower than the control group's (P < .05). After treatment, the levels of serum inflammatory factor indicators of CRP, PCT, and TNF- α in both groups were decreased compared with those before treatment; while comparing the above indicators between the groups, it was found that the values in the study group were lower (all P < .05). After treatment, the scores of symptoms such as cough, expectoration, and shortness of breath in both groups of patients were significantly lower than before treatment, while compared to the control group, the scores of all symptoms were lower in the study group (P < .05). After treatment, compared with FEV1, FEV1/FVC, PaO2, and PaCO2 before treatment, the above indicators in both groups were significantly improved. However, compared with various indicators in the control group, the values of FEV1, FEV1/FVC, and PaO2 in the study group were higher, while the values of PaCO2 in the study group were lower (all P < .05). After treatment, the measured values of indicators such as thoracic compliance, lung compliance, and total compliance in the two groups were significantly higher compared with those before the treatment, while compared to the control group, the values of all indicators in the study group were higher (P < .05). After treatment, compared with the control group's monitoring of various indicators of nighttime sleep, the study group obtained better data on monitoring of sleep latency and actual sleep duration. The group obtained lower scores in sleep quality evaluation, while the two groups significantly improved their sleep-related data in night-time monitoring and evaluation compared to those before treatment, with all P < .05. After treatment, the scores in various aspects of the quality of life of patients in both groups were significantly increased compared to those before treatment, and after comparing the scores of various quality of life between the two groups, it was found that the study group was higher than the control group (all P < .05).
CONCLUSION
After the onset of COPD, doxofylline treatment can achieve better effects than aminophylline treatment.
PubMed: 38607196
DOI: No ID Found -
Fundamental & Clinical Pharmacology Mar 2024Adenosinergic system has been implicated in the pathophysiology of bipolar disorder and drugs that affect adenosine neurotransmission have shown some efficacy as add-on...
BACKGROUND
Adenosinergic system has been implicated in the pathophysiology of bipolar disorder and drugs that affect adenosine neurotransmission have shown some efficacy as add-on therapy in manic patients.
OBJECTIVE
Thus, the aim of the present study was to screen adenosinergic drugs for antimanic-like effect in methylphenidate (MPH)-induced hyperlocomotion in mice.
METHODS
Male and female Swiss mice received a single allopurinol (50 and 200 mg/kg, ip), dipyridamole (20 mg/kg, ip), or inosine (50 mg/kg, ip) administration before an acute MPH challenge (5 mg/kg, sc). In experiments with repeated treatment, male mice received a daily administration of allopurinol (25 and 50 mg/kg, ip), dipyridamole (20 mg/kg, ip), or inosine (50 mg/kg, ip) for 14 days. Finally, pretreatment with aminophylline (2 mg/kg, sc), an unspecific adenosine receptor antagonist, was used to evaluate a putative adenosinergic mediation. Locomotor activity was measured in the automated activity chamber for 20 min.
RESULTS
Acute and repeated dipyridamole reduced the increase in locomotor activity induced by MPH, while allopurinol and inosine had no effect. Aminophylline blocked the effect of dipyridamole in MPH-induced hyperlocomotion.
CONCLUSION
The present results suggest that dipyridamole may have an antimanic-like effect through adenosine receptors and reinforce the proposal that the adenosine system may be an interesting target for new antimanic drugs.
PubMed: 38472106
DOI: 10.1111/fcp.13001 -
Applied Spectroscopy May 2024Aminophylline (AMP) is a bronchodilator. The therapeutic and toxic doses are very close. Therefore, therapeutic drug monitoring (TDM) of AMP is essential in clinical...
Aminophylline (AMP) is a bronchodilator. The therapeutic and toxic doses are very close. Therefore, therapeutic drug monitoring (TDM) of AMP is essential in clinical practice. Microgels were synthesized by free radical precipitation polymerization. Silver@poly(-isopropyl acrylamide) (Ag@PNIPAM) hybrid microgels were obtained by loading silver (Ag) nanoparticles into the three-dimensional network of the microgels by in situ reduction. The microgel is a three-dimensional reticular structure with tunable pore size, large specific surface area, and good biocompatibility, which can be used as a sorbent for solid-phase extraction (SPE) of target molecules in complex matrices and as a surface-enhanced Raman spectroscopy (SERS) substrate. We optimized the conditions affecting SERS enhancement, such as silver nitrate (AgNO) concentration and SPE time, according to the SERS strategy of Ag@PNIPAM hybrid microgels to achieve label-free TDM for trace AMP in human serum. The results showed good linearity between the logarithmic concentration of AMP and its SERS intensity in the range of 1-1.1 × 10 µg/mL, with a correlation coefficient () of 0.9947 and a low detection limit of 0.61 µg/mL. The assay accuracy was demonstrated by spiking experiments, with recoveries ranging from 93.0 to 101.8%. The method is rapid, sensitive, reproducible, requires simple sample pretreatment, and has good potential for use in clinical treatment drug monitoring.
Topics: Aminophylline; Humans; Spectrum Analysis, Raman; Solid Phase Extraction; Silver; Limit of Detection; Microspheres; Hydrogels; Metal Nanoparticles; Acrylic Resins; Drug Monitoring; Bronchodilator Agents
PubMed: 38389424
DOI: 10.1177/00037028241233016