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Clinical Pharmacology and Therapeutics May 2018We hypothesized that concomitant pharmacological inhibition of the endothelin and adenosine pathway is safe and improves exercise performance in hypoxic humans, via a... (Randomized Controlled Trial)
Randomized Controlled Trial
We hypothesized that concomitant pharmacological inhibition of the endothelin and adenosine pathway is safe and improves exercise performance in hypoxic humans, via a mechanism that does not involve augmentation of blood oxygenation. To test this hypothesis, we established safety and drug interactions for aminophylline (500 mg) plus ambrisentan (5 mg) in normoxic volunteers. Subsequently, a placebo-controlled study was employed to test the combination in healthy resting and exercising volunteers at simulated altitude (4,267 m). No serious adverse events occurred. Drug interaction was minimal or absent. Aminophylline alleviated hypoxia-induced headaches. Aminophylline, ambrisentan, and their combination all significantly (P < 0.05 vs. placebo) improved submaximal hypoxic exercise performance (19.5, 20.6, and 19.1% >placebo). Single-dose ambrisentan increased blood oxygenation in resting, hypoxic subjects. We conclude that combined aminophylline and ambrisentan offer promise to safely increase exercise capacity in hypoxemic humans without relying on increasing blood oxygen availability.
Topics: Adenosine; Adolescent; Adult; Altitude; Aminophylline; Double-Blind Method; Drug Therapy, Combination; Endothelins; Exercise; Female; Humans; Hypoxia; Male; Middle Aged; Phenylpropionates; Pyridazines; Signal Transduction; Young Adult
PubMed: 28857147
DOI: 10.1002/cpt.860 -
Kidney Research and Clinical Practice Sep 2020Acute kidney injury (AKI) in the pediatric population is a relatively common phenomenon. Specifically, AKI has been found in increasing numbers within the pediatric... (Review)
Review
Acute kidney injury (AKI) in the pediatric population is a relatively common phenomenon. Specifically, AKI has been found in increasing numbers within the pediatric population following cardiac surgery, with up to 43% of pediatric patients developing AKI post-cardiac surgery. However, recent advances have allowed for the identification of risk factors. These can be divided into preoperative, intraoperative, and postoperative factors. Although the majority of pediatric patients developing AKI after cardiac surgery completely recover, this condition is associated with worse outcomes. These include fluid overload and increased mortality and result in longer hospital and intensive care unit stays. Detecting the presence of AKI has advanced; use of relatively novel biomarkers, including neutrophil gelatinase associated lipocalin, has shown promise in detecting more subtle changes in kidney function when compared to conventional methods. While a single, superior treatment has not been elucidated yet, novel functions of medications, including fenoldopam, theophylline and aminophylline, have been shown to have better outcomes for these patients. With the recent advances in identification of risk factors, outcomes, diagnosis, and management, the medical community can further explain the complexities of AKI in the pediatric population post-cardiac surgery.
PubMed: 32773391
DOI: 10.23876/j.krcp.20.053 -
International Journal of Health Sciences 2020Acute kidney injury (AKI) is a major cause of morbidity and mortality. Whether aminophylline administration can prevent or treat AKI among pediatric patients are not... (Review)
Review
OBJECTIVES
Acute kidney injury (AKI) is a major cause of morbidity and mortality. Whether aminophylline administration can prevent or treat AKI among pediatric patients are not clear. This meta-analysis aimed to assess the efficacy and effectiveness of aminophylline for pediatric AKI.
METHODS
We carried out a systematic search of six databases: PubMed, EMBASE/Excerpta Medica, Scopus, Cochrane library, and Google Scholar from January 1995 up till May 2019. Summary measures of risk ratios and standard mean difference were calculated using the random effects model.
RESULTS
We identified seven papers containing data on aminophylline use in children with AKI. Meta-analysis of single-arm studies indicated no statistically significant difference in mean rate of serum creatinine clearance (-0.39 [-0.80-1.58], = 0.52), mean urine output (1.99 [-1.43-5.42]; = 0.25), or mean blood urea nitrogen levels (0.83 [-1.86-3.03], = 0.54) before and after aminophylline administration. However, among double-arm studies, aminophylline administration in the intervention arm significantly reduced the serum creatinine level as compared to control arm (mean diff = -34 [-55.18--12.83]; = 0.002). Mean urine output (-112.68 [-27.43-48.9], = 0.17), incidence of AKI (RR = 1.05 [0.80-1.37], = 0.72), and mortality rates (RR = 0.79 [0.42-1.47], = 0.45) were found to be statistically insignificant.
CONCLUSIONS
Aminophylline administration in children with AKI reduces serum creatinine level without significant adverse effects or effect on the incidence of AKI, urine output, or mortality. Further, large-scale well-planned randomized controlled trials are needed to evaluate its use and its potential long-term effects.
PubMed: 33192231
DOI: No ID Found -
Sao Paulo Medical Journal = Revista... Mar 2018Cardiac arrest is associated with high morbidity and mortality and imposes a significant burden on the healthcare system. Management of cardiac arrest patients is... (Review)
Review
CONTEXT AND OBJECTIVE
Cardiac arrest is associated with high morbidity and mortality and imposes a significant burden on the healthcare system. Management of cardiac arrest patients is complex and involves approaches with multiple interventions. Here, we aimed to summarize the available evidence regarding the interventions used in cardiac arrest cases.
DESIGN AND SETTING
Review of systematic reviews (SRs), conducted in the Discipline of Evidence-Based Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo.
METHODS
A systematic search was conducted to identify all Cochrane SRs that fulfilled the inclusion criteria. Titles and abstracts were screened by two authors.
RESULTS
We included nine Cochrane SRs assessing compression techniques or devices (three SRs), defibrillation (two SRs) and other interventions (two SRs on hypothermia interventions, one on airway management and one on pharmacological intervention). The reviews included found qualities of evidence ranging from unknown to high, regarding the benefits of these interventions.
CONCLUSION
This review included nine Cochrane systematic reviews that provided a diverse range of qualities of evidence (unknown to high) regarding interventions that are used in management of cardiac arrest. High-quality evidence was found by two systematic reviews as follows: (a) increased survival until hospital discharge with continuous compression, compared with interrupted chest compression, both administered by an untrained person and (b) no difference regarding the return of spontaneous circulation, comparing aminophylline and placebo, for bradyasystolic patients under cardiac arrest. Further studies are needed in order to reach solid conclusions.
Topics: Evidence-Based Medicine; Heart Arrest; Humans; Review Literature as Topic
PubMed: 29791610
DOI: 10.1590/1516-3180.2018.0083230318 -
The Cochrane Database of Systematic... Oct 2023Methylxanthines, including caffeine, theophylline, and aminophylline, work as stimulants of the respiratory drive, and decrease apnea of prematurity, a developmental... (Review)
Review
BACKGROUND
Methylxanthines, including caffeine, theophylline, and aminophylline, work as stimulants of the respiratory drive, and decrease apnea of prematurity, a developmental disorder common in preterm infants. In particular, caffeine has been reported to improve important clinical outcomes, including bronchopulmonary dysplasia (BPD) and neurodevelopmental disability. However, there is uncertainty regarding the efficacy of caffeine compared to other methylxanthines.
OBJECTIVES
To assess the effects of caffeine compared to aminophylline or theophylline in preterm infants at risk of apnea, with apnea, or in the peri-extubation phase.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, Epistemonikos, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and clinicaltrials.gov in February 2023. We also checked the reference lists of relevant articles to identify additional studies.
SELECTION CRITERIA
Studies: randomized controlled trials (RCTs) and quasi-RCTs Participants: infants born before 34 weeks of gestation for prevention and extubation trials, and infants born before 37 weeks of gestation for treatment trials Intervention and comparison: caffeine versus theophylline or caffeine versus aminophylline. We included all doses and duration of treatment.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. We evaluated treatment effects using a fixed-effect model with risk ratio (RR), risk difference (RD), and 95% confidence intervals (CI) for categorical data, and mean, standard deviation, and mean difference for continuous data. We used the GRADE approach to evaluate the certainty of evidence.
MAIN RESULTS
We included 22 trials enrolling 1776 preterm infants. The indication for treatment was prevention of apnea in three studies, treatment of apnea in 13 studies, and extubation management in three studies. In three studies, there were multiple indications for treatment, and in one study, the indication for treatment was unclear. In 19 included studies, the infants had a mean gestational age between 28 and 32 weeks and a mean birth weight between 1000 g and 1500 g. One study's participants had a mean gestational age of more than 32 weeks, and two studies had participants with a mean birth weight of 1500 g or more. Caffeine administrated for any indication may result in little to no difference in all-cause mortality prior to hospital discharge compared to other methylxanthines (RR 1.12, 95% CI 0.68 to 1.84; RD 0.02, 95% CI -0.05 to 0.08; 2 studies, 396 infants; low-certainty evidence). Only one study enrolling 79 infants reported components of the outcome moderate to severe neurodevelopmental disability at 18 to 26 months. The evidence is very uncertain about the effect of caffeine on cognitive developmental delay compared to other methylxanthines (RR 0.17, 95% CI 0.02 to 1.37; RD -0.12, 95% CI -0.24 to 0.01; 1 study, 79 infants; very low-certainty evidence). The evidence is very uncertain about the effect of caffeine on language developmental delay compared to other methylxanthines (RR 0.76, 95% CI 0.37 to 1.58; RD -0.07, 95% CI -0.27 to 0.12; 1 study, 79 infants; very low-certainty evidence). The evidence is very uncertain about the effect of caffeine on motor developmental delay compared to other methylxanthines (RR 0.50, 95% CI 0.13 to 1.96; RD -0.07, 95% CI -0.21 to 0.07; 1 study, 79 infants; very low-certainty evidence). The evidence is very uncertain about the effect of caffeine on visual and hearing impairment compared to other methylxanthines. At 24 months of age, visual impairment was seen in 8 out of 11 infants and 10 out of 11 infants in the caffeine and other methylxanthines groups, respectively. Hearing impairment was seen in 2 out of 5 infants and 1 out of 1 infant in the caffeine and other methylxanthines groups, respectively. No studies reported the outcomes cerebral palsy, gross motor disability, and mental development. Compared to other methylxanthines, caffeine may result in little to no difference in BPD/chronic lung disease, defined as 28 days of oxygen exposure at 36 weeks' postmenstrual age (RR 1.40, 95% CI 0.92 to 2.11; RD 0.04, 95% CI -0.01 to 0.09; 3 studies, 481 infants; low-certainty evidence). The evidence is very uncertain about the effect of caffeine on side effects (tachycardia, agitation, or feed intolerance) leading to a reduction in dose or withholding of methylxanthines compared to other methylxanthines (RR 0.17, 95% CI 0.02 to 1.32; RD -0.29, 95% CI -0.57 to -0.02; 1 study, 30 infants; very low-certainty evidence). Caffeine may result in little to no difference in duration of hospital stay compared to other methylxanthines (median (interquartile range): caffeine 43 days (27.5 to 61.5); other methylxanthines 39 days (28 to 55)). No studies reported the outcome seizures.
AUTHORS' CONCLUSIONS
Although caffeine has been shown to improve important clinical outcomes, in the few studies that compared caffeine to other methylxanthines, there might be little to no difference in mortality, bronchopulmonary dysplasia, and duration of hospital stay. The evidence is very uncertain about the effect of caffeine compared to other methylxanthines on long-term development and side effects. Although caffeine or other methylxanthines are widely used in preterm infants, there is little direct evidence to support the choice of which methylxanthine to use. More research is needed, especially on extremely preterm infants born before 28 weeks of gestation. Data from four ongoing studies might provide more evidence on the effects of caffeine or other methylxanthines.
Topics: Humans; Infant, Newborn; Aminophylline; Apnea; Birth Weight; Bronchopulmonary Dysplasia; Caffeine; Hearing Loss; Infant, Extremely Premature; Theophylline; Randomized Controlled Trials as Topic
PubMed: 37791592
DOI: 10.1002/14651858.CD015462.pub2 -
Evidence-based Complementary and... 2022In this study, we aimed to determine the effects of intermittent hypoxia (IH) on hepatic cytochrome P450 1A2 (CYP1A2) expression and the pharmacokinetics of...
PURPOSE
In this study, we aimed to determine the effects of intermittent hypoxia (IH) on hepatic cytochrome P450 1A2 (CYP1A2) expression and the pharmacokinetics of CYP1A2-mediated aminophylline and warfarin and in a rabbit model of obstructive sleep apnea.
MATERIALS
Human normal liver (LO-2) cells were exposed to 30 min each of 1%, 1-21%, 21%, and 21-1% O, and then, CYP1A2 expression and drug concentrations were analyzed. We compared the pharmacokinetic parameters of drugs administered to normoxic rabbits and those exposed to 10 min of IH during which the oxygen level fluctuated from 21% to 8%-10% ( = 10 per group).
RESULT
s. The expression of CYP1A2 protein was significantly reduced in the IH compared with the normoxic cells (0.56 ± 0.11 vs. 1.27 ± 0.17, < 0.001). Aminophylline was more abundant in cell culture supernatants after 48 h of IH than in those under normoxia. The , AUC, and Ke values for aminophylline were significantly higher in the IH group.
CONCLUSION
Intermittent hypoxia inhibits hepatic CYP1A2 expression and delays aminophylline metabolism, suggesting that the impact of IH on the expression of CYP enzymes should be closely monitored in clinical practice.
PubMed: 35529917
DOI: 10.1155/2022/2782702 -
Early Human Development Aug 2016This study investigated the effect of aminophylline on behaviour and autonomic function in the preterm period.
AIM
This study investigated the effect of aminophylline on behaviour and autonomic function in the preterm period.
METHOD
Subjects were preterm infants cared for in the Oita University hospital from August 2012 to October 2014. The group that was administered aminophylline (Am+) and the group that received no aminophylline (Am-) included 11 cases that exhibited a mean gestational age of 28weeks 5days and a mean birth weight of 1109g and 8 cases that exhibited a mean gestational age of 30weeks 5days and a mean birth weight of 1223g, respectively. Intravenous aminophylline was administered continuously at a dose of 4-6mg/kg/day followed by oral therapy when the infant suffered repetitive apnoea. Two-hour video recordings were obtained every 2weeks, and electrocardiograms were performed simultaneously. Onset-offset and tremulous movements in general movement (GM) optimality list were used as indices of behaviour. Autonomic functions were investigated via heart-rate and heart-rate variability measurements using frequency domain spectral analysis and the MemCalc method. We compared indices in 4 periods: 30-31, 32-33, 34-35 and 36-37weeks gestation.
RESULTS
The Am+ group exhibited significantly low optimality of tremulous movements at 32-33weeks gestation. The autonomic parameters did not differ significantly between the Am+ and Am- groups. There was no significant correlation between GMs optimality score and serum theophylline concentration.
CONCLUSION
Aminophylline administration was associated with transient irritable behaviour without autonomic changes in the preterm period.
Topics: Aminophylline; Female; Heart Rate; Humans; Infant, Newborn; Infant, Premature; Irritable Mood; Male; Movement
PubMed: 27390110
DOI: 10.1016/j.earlhumdev.2016.04.011 -
Anesthesia and Pain Medicine Apr 2023Post-dural puncture headache (PDPH) is one of the most common complications in patients undergoing spinal anesthesia. The present systematic review and meta-analysis...
BACKGROUND
Post-dural puncture headache (PDPH) is one of the most common complications in patients undergoing spinal anesthesia. The present systematic review and meta-analysis aimed to assess the therapeutic and prophylactic effects of aminophylline and theophylline on PDPH.
METHODS
Relevant studies were identified by searching the following electronic databases, without language restriction, until June 2020: Scopus, EMBASE, MEDLINE, Google Scholar, Web of Science, Cochrane Library-CENTRAL, and CINAHL Complete. Random effects models were used to calculate the standardized mean difference (SMD) and risk ratios (RRs) with 95% confidence intervals (95% CI) to assess the therapeutic and prophylactic effects of aminophylline and theophylline on PDPH, respectively. The Cochrane tool was used for the quality assessment of the included studies. The certainty of the evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation method.
RESULTS
Of the 1,349 initial records, 15 met our eligibility criteria (6 studies on therapeutic and 9 on prophylactic effects). A significant reduction in the pain score was observed following aminophylline/theophylline treatment (SMD = -1.67; 95% CI, -2.28 to -1.05; P < 0.001, I2 = 84.7%; P < 0.001). Subgroup analysis revealed that the therapeutic effect was significantly higher when these agents were compared to placebo than when conventional therapies were used. The risk of PDPH after aminophylline administration was not significantly reduced (RR = 0.74; 95% CI, 0.42 to 1.31; P = 0.290).
CONCLUSIONS
Theophylline and aminophylline have therapeutic, but not prophylactic, effects on PDPH.
PubMed: 37183286
DOI: 10.17085/apm.22247 -
European Respiratory Review : An... Jun 2018Theophylline can still have a role in the management of stable chronic obstructive pulmonary disease (COPD), but its use remains controversial, mainly due to its narrow... (Meta-Analysis)
Meta-Analysis Review
Theophylline can still have a role in the management of stable chronic obstructive pulmonary disease (COPD), but its use remains controversial, mainly due to its narrow therapeutic window. Doxofylline, another xanthine, is an effective bronchodilator and displays a better safety profile than theophylline. Therefore, we performed a quantitative synthesis to compare the efficacy and safety profile of different xanthines in COPD.The primary end-point of this meta-analysis was the impact of xanthines on lung function. In addition, we assessed the risk of adverse events by normalising data on safety as a function of person-weeks. Data obtained from 998 COPD patients were selected from 14 studies and meta-analysed using a network approach.The combined surface under the cumulative ranking curve (SUCRA) analysis of efficacy (change from baseline in forced expiratory volume in 1 s) and safety (risk of adverse events) showed that doxofylline was superior to aminophylline (comparable efficacy and significantly better safety), bamiphylline (significantly better efficacy and comparable safety), and theophylline (comparable efficacy and significantly better safety).Considering the overall efficacy/safety profile of the investigated agents, the results of this quantitative synthesis suggest that doxofylline seems to be the best xanthine for the treatment of COPD.
Topics: Bronchodilator Agents; Forced Expiratory Volume; Humans; Lung; Pulmonary Disease, Chronic Obstructive; Recovery of Function; Theophylline; Treatment Outcome; Xanthines
PubMed: 29720510
DOI: 10.1183/16000617.0010-2018 -
The Annals of Pharmacotherapy Mar 2019The latest aminophylline shortage has prompted a need for alternative reversal agents for pharmacological stress testing. Cardiac stress testing is common for diagnosis...
The latest aminophylline shortage has prompted a need for alternative reversal agents for pharmacological stress testing. Cardiac stress testing is common for diagnosis and prognosis in patients with coronary heart disease. Options for pharmacological stress test agents include adenosine, regadenoson, dipyridamole, and dobutamine, whereas aminophylline is the recommended reversal agent. Adenosine and dobutamine can be used as alternatives to regadenoson and dipyridamole to decrease or eliminate the use of aminophylline. Alternatives to aminophylline include theophylline and caffeine. It is important to efficiently identify alternatives during a drug shortage to maintain optimal patient outcomes.
Topics: Aminophylline; Caffeine; Coronary Disease; Drug Utilization; Exercise Test; Female; Humans; Male; Theophylline; Vasodilator Agents
PubMed: 30304941
DOI: 10.1177/1060028018806624