Effects of aminophylline therapy on urine output and kidney function in children with acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is a frequent complication of children admitted to the paediatric intensive care unit. One key management modality of AKI is the use of diuretics to reduce fluid overload. Aminophylline, a drug that is well known for its use in the treatment of bronchial asthma, is also purported to have diuretic effects on the kidneys. This retrospective cohort study assesses the effect of aminophylline in critically ill children with AKI. METHODS: A retrospective chart review of children admitted to the paediatric intensive care unit of the Red Cross War Memorial Children's Hospital (RCWMCH) with AKI who received aminophylline (from 2012 to June 2018) was carried out. Data captured and analyzed included demographics, underlying disease conditions, medications, urine output, fluid balance, and kidney function. RESULTS: Data from thirty-four children were analyzed. Urine output increased from a median of 0.4 mls/kg/hr [IQR: 0.1, 1.1] at six hours prior to aminophylline administration to 0.6 mls/kg/hr [IQR: 0.2, 1.9] at six hours and 1.6 mls/kg/hr [IQR:0.2, 4.2] at twenty-four hours post aminophylline therapy. The median urine output significantly varied across the age groups over the 24-h time period post-aminophylline, with the most response in the neonates. There was no significant change in serum creatinine levels six hours post-aminophylline administration [109(IQR: 77, 227)-125.5(IQR: 82, 200) micromole/l] P-value = 0.135. However, there were significant age-related changes in creatinine levels at six hours post-aminophylline therapy. CONCLUSIONS: Aminophylline increases urine output in critically ill children with AKI. A higher resolution version of the Graphical abstract is available as Supplementary information.

Aminophylline suppresses chronic renal failure progression by activating SIRT1/AMPK/mTOR-dependent autophagy.

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.

Adenosine and γ-aminobutyric acid partially regulate metabolic and ventilatory responses of Damaraland mole-rats to acute hypoxia.

Fossorial Damaraland mole-rats (Fukomys damarensis) mount a robust hypoxic metabolic response (HMR) but a blunted hypoxic ventilatory response (HVR) to acute hypoxia. Although these reflex physiological responses have been described previously, the underlying signalling pathways are entirely unknown. Of particular interest are contributions from γ-aminobutyric acid (GABA), which is the primary inhibitory neurotransmitter in the nervous system of most adult mammals, and adenosine, the accumulation of which increases during hypoxia as a breakdown product of ATP. Therefore, we hypothesized that GABAergic and/or adenosinergic signalling contributes to the blunted HVR and robust HMR in Damaraland mole-rats. To test this hypothesis, we injected adult animals with saline alone (controls), or 100 mg kg-1 aminophylline or 1 mg kg-1 bicuculline, to block adenosine or GABAA receptors, respectively. We then used respirometry, plethysmography and thermal RFID probes to non-invasively measure metabolic, ventilator and thermoregulatory responses, respectively, to acute hypoxia (1 h in 5 or 7% O2) in awake and freely behaving animals. We found that bicuculline had relatively minor effects on metabolism and thermoregulation but sensitized ventilation such that the HVR became manifest at 7% instead of 5% O2 and was greater in magnitude. Aminophylline increased metabolic rate, ventilation and body temperature in normoxia, and augmented the HMR and HVR. Taken together, these findings indicate that adenosinergic and GABAergic signalling play important roles in mediating the robust HMR and blunted HVR in Damaraland mole-rats.

Ultrasensitive SERS substrate for label-free therapeutic drug monitoring of chlorpromazine hydrochloride and aminophylline in human serum.

Surface-enhanced Raman spectroscopy (SERS) has been widely used in the field of therapeutic drug monitoring (TDM) because of its powerful fingerprinting capability. In this paper, we used an in situ synthesis method to anchor Ag nanoparticles (AgNPs) on the surface of MIL-101(Cr) to obtain MIL-101(Cr)@Ag. Owing to the large specific surface area and ultra-high porosity of MIL-101(Cr)@Ag, we developed a method for the determination of chlorpromazine hydrochloride (CPZ) and aminophylline (AMP) in human serum by using it as a solid-phase extraction sorbent and SERS substrate. The label-free TDM-SERS method was able to evaluate the levels of CPZ and AMP in serum samples with detection limits as low as 8.91 × 10-2 µg/mL and 3.4 × 10-2 µg/mL, respectively. In addition, influencing factors including sample solution pH, AgNO3 concentration, drug adsorption time, and the amount of sample solution were optimized. This protocol provides a new method with good selectivity, stability, reproducibility, homogeneity, and sensitivity for the determination of small-molecule drug content in serum samples. This label-free TDM-SERS method will help to achieve rapid individualized dosing regimens in clinical practice and has potential applications in the field of TDM.

The diuretic effect of adding aminophylline or theophylline to furosemide in pediatric populations: a systematic review.

The diuretic effect of the combined furosemide and aminophylline/theophylline among pediatric patients remains unclear. The primary aim of this systematic review was to examine the clinical diuretic effects (urine output and fluid balance) of co-administration of furosemide and aminophylline/theophylline as compared to furosemide alone in pediatric population. Ovid MEDLINE, CENTRAL, and EMBASE were searched from its inception until March 2022 for observational studies and randomized controlled trials (RCTs) comparing the administration of furosemide versus furosemide and aminophylline/theophylline in pediatric population. Case reports, case series, commentaries, letters to editors, systematic reviews, and meta-analyses were excluded. Five articles with a total sample population of 187 patients were included in this systematic review. As compared to the furosemide alone, our pooled data demonstrated that co-administration of furosemide and aminophylline/theophylline was associated with higher urine output (mean difference: 2.91 [90% CI 1.54 to 4.27], p < 0.0001, I2 = 90%) and a more negative fluid balance (mean difference - 28.27 [95% CI: - 46.21 to - 10.33], p = 0.002, I2 = 56%) than those who received furosemide alone. CONCLUSION: This is the first paper summarizing the evidence of combined use of furosemide with aminophylline/theophylline in pediatric population. Our systematic review demonstrated that the co-administration of furosemide and aminophylline/theophylline could potentially yield better diuretic effects of urine output and negative fluid balance than furosemide alone in pediatric patients with fluid overload. Given the substantial degree of heterogeneity and low level of evidence, future adequately powered trials are warranted to provide evidence regarding the combined use of aminophylline/theophylline and furosemide as diuretic in the pediatric population. WHAT IS KNOWN: • Fluid overload is associated with poor prognosis for children in the intensive care unit. • The ineffective result of furosemide alone, even at high dose, as diuretic agent for children with diuretic resistant fluid overload in the intensive care unit. WHAT IS NEW: • This is the first systematic review that compares furosemide alone and co-administration of furosemide and aminophylline/theophylline. • This paper showed potential benefit of co-administration of furosemide and aminophylline/theophylline promoting urine output and negative fluid balance compared to furosemide alone.

A mix of aminophylline and heparin plus nitroglycerin can reduce bradycardia during rotational atherectomy on the right coronary artery and dominant circumflex artery.

BACKGROUND: Rotational atherectomy (RA) may cause bradyarrhythmias and transitory atrioventricular block when performed in the right coronary artery (RCA) or a dominant circumflex (CX) coronary artery. However, there are no studies of a solution that can prevent coronary flow deterioration and bradycardia complications that may occur during RA. We aimed to create an alternative rota-flush solution to minimize the risk of bradycardia and complete atrioventricular block (AVB) that can occur during RA. MATERIALS AND METHODS: The study comprised 60 patients who were randomly divided into two groups: 30 received rotaphylline (= 240 mg aminophylline, 10,000 U unfractionated heparin, and 2000 mcg nitroglycerin to 1000 mL saline), and 30 received the traditional rota-flush (= 10,000 U unfractionated heparin, 2000 mcg nitroglycerin, and 1000 mL saline). The incidence of bradycardia or high-grade AVB (HAVB) during RA, coronary slow-flow phenomenon or no-reflow phenomenon, and coronary spasm were the primary endpoints of the study. Procedure success and RA-related procedural complications were secondary endpoints. RESULTS: The use of rotaphylline was an independent predictor of bradycardia and HAVB after accounting for all other factors (OR: 0.47, 95% CI: 0.24-0.79, p < 0.001). Lesion length (OR: 2.17, 95% CI: 1.24-3.04, p < 0.001), burr-to-artery ratio (OR: 0.59, 95% CI: 0.39-1.68, p < 0.001), and total run duration (OR: 0.79, 95% CI: 0.35-1.43, p < 0.001) were additional independent predictors. CONCLUSION: Bradycardia and the development of HAVB may be avoided by rotaphylline intracoronary infusion during RA applied to the RCA and dominant CX lesions. Multicenter studies including sizable patient populations should be conducted to validate the present findings.

Effects of low-dose furosemide combined with aminophylline on the renal function in septic shock patients.

BACKGROUND: To investigate the effects of low-dose furosemide and aminophylline on the renal function in patients with septic shock. METHODS AND RESULTS: A total of 109 eligible septic shock patients in the intensive care unit were randomly divided into a control group (n = 55) and an intervention group (n = 54). The control group received normal saline, and the intervention group received low-dose furosemide (0.048 mg/kg.h-1) with aminophylline (0.3 mg/kg.h-1). The primary outcomes included the levels of serum creatinine (Scr), creatinine clearance rate (Ccr), blood urea nitrogen (BUN), glomerular filtration rate (GFR), and urine output on admission and on days 3, 7 and 14. The secondary outcomes were the sequential organ failure assessment (SOFA) scores, continuous renal replacement therapy (CRRT) time and intensive care unit (ICU) mortality, hospital mortality and 28-day mortality. There were no significant differences in the levels of Scr, Ccr, BUN, or GFR between the two groups, while the urine output was higher in the intervention group on days 3, 7, and 14. Compared with the control group, the SOFA scores, ICU mortality, hospital mortality and 28-day mortality were significantly lower in the intervention group on days 3, 7, and 14, the CRRT time was shorter, and the cumulative fluid balance was lower on days 3 and 7 in the intervention group. CONCLUSIONS: Although low-dose furosemide and aminophylline have fewer protective effects on the renal function in septic shock patients, they could reduce the CRRT time and improve the prognosis.

Comparison of the effects of caffeine, aminophylline, and saline on the recovery from total intravenous anesthesia in laparoscopic surgeries: A randomized controlled trial.

Background and Aims: The return of consciousness (ROC) after general anesthesia (GA) is by stopping the administration of anesthetic agents. At present, no drug is given to reverse the loss of consciousness produced by general anesthetic agents. This study is conducted to find whether caffeine and aminophylline hasten the ROC. Material and Methods: This study was conducted on 75 American Society of Anesthesiologists (ASA) I and II female patients undergoing laparoscopic hysterectomy, aged between 18 and 60 years. The patients were divided into three equal groups (Group C: caffeine citrate, Group A: aminophylline, and Group S: saline) of 25 each by a computer-generated random number table. GA was induced with propofol, fentanyl, and maintained with propofol infusion. On completion of the surgery, the neuromuscular blocking agent was reversed and then the infusion of propofol was stopped. The study drug was administered intravenously when the BIS 60 was achieved. Time to achieve BIS 90, return of first gag reflex, eye-opening on verbal command, and extubation after study drug administration were noted. Hemodynamic parameters and SpO2 were also monitored. Results: The time for BIS 60 to 90 was 10 (4.25) min in the caffeine group, 13 (4.25) min in the aminophylline group, and 26 (9.0) min in the saline group. The time to return of gag reflex and time to extubation were shorter in the caffeine and aminophylline group compared to the saline group. The time to eye-opening on verbal command was shorter in the aminophylline group compared to the saline group. Hemodynamic parameters after infusion of the study drug were comparable in all three groups. Conclusion: Caffeine hastens the recovery from total intravenous anesthesia with propofol and fentanyl in laparoscopic hysterectomy as effectively as aminophylline.

Aminophylline at clinically relevant concentrations affects inward rectifier potassium current in a dual way.

Bronchodilator aminophylline may induce atrial or less often ventricular arrhythmias. The mechanism of this proarrhythmic side effect has not been fully explained. Modifications of inward rectifier potassium (Kir) currents including IK1 are known to play an important role in arrhythmogenesis; however, no data on the aminophylline effect on these currents have been published. Hence, we tested the effect of aminophylline (3-100 µM) on IK1 in enzymatically isolated rat ventricular myocytes using the whole-cell patch-clamp technique. A dual steady-state effect of aminophylline was observed; either inhibition or activation was apparent in individual cells during the application of aminophylline at a given concentration. The smaller the magnitude of the control IK1, the more likely the activation of the current by aminophylline and vice versa. The effect was reversible; the relative changes at -50 and -110 mV did not differ. Using IK1 channel population model, the dual effect was explained by the interaction of aminophylline with two different channel populations, the first one being inhibited and the second one being activated. Considering various fractions of these two channel populations in individual cells, varying effects observed in the measured cells could be simulated. We propose that the dual aminophylline effect may be related to the direct and indirect effect of the drug on various Kir2.x subunits forming the homo- and heterotetrameric IK1 channels in a single cell. The observed IK1 changes induced by clinically relevant concentrations of aminophylline might contribute to arrhythmogenesis related to the use of this bronchodilator in clinical medicine.

Intravesical aminophylline instillation as an alternative for balloon dilatation prior to semi-rigid ureteroscopic management of distal ureteral stones.

PURPOSE: In a randomized controlled trial, we evaluated the effect of intravesical aminophylline instillation (IVAI) on intraureteral pressure of lower ureter and its use as an alternative to balloon dilatation after failure of advancing semi-rigid ureteroscope through the ureteric orifice without endodilatation. METHODS: Our study included 83 patients with juxta-vesical distal ureteral calculi requiring endodilatation after unsuccessfully introducing the semi-rigid ureteroscope through the ureteric orifice. Patients were randomized into two groups: group A (study group) included 41 patients, where IVAI was used to dilate the ureter and facilitate ureteroscopy (the intraureteral pressure was measured using a pressure transducer connected to an invasive pressure monitor before and 5 min after IVAI), whereas group B (control group) included 42 patients, where balloon dilatation was used prior to ureteroscopy. Perioperative surgical outcomes of ureteroscopy were evaluated in both groups. RESULTS: A statistically significant decrease in mean intraureteral pressure of intravesical ureter was found after IVAI from 12.34 mmHg ± 1.94 before injection to 8.46 mmHg ± 1.94 after injection (P < 0.001). Ureteral injuries, postoperative pain and hematuria were statistically significantly less among the study group compared to the control group (P < 0.05). We did not find statistically significant differences in operative time, need for DJ ureteral stenting or stone-free rate between both groups and no perioperative side effects were associated with IVAI. CONCLUSION: In ureteroscopic management of distal ureteral stones, intravesical aminophylline instillation is safe, inexpensive and effective in reducing intraureteral pressure and achieves comparable outcomes to balloon dilatation with less ureteral injuries, postoperative pain and hematuria.

Use of ketamine in patients with refractory severe asthma exacerbations: systematic review of prospective studies.

PURPOSE: Asthma is a heterogeneous disease with a wide range of symptoms. Severe asthma exacerbations (SAEs) are characterized by worsening symptoms and bronchospasm requiring emergency department visits. In addition to conventional strategies for SAEs (inhaled ß-agonists, anticholinergics, and systemic corticosteroids), another pharmacological option is represented by ketamine. We performed a systematic review to explore the role of ketamine in refractory SAEs. METHODS: We performed a systematic search on PubMed and EMBASE up to August 12th, 2021. We selected prospective studies only, and outcomes of interest were oxygenation/respiratory parameters, clinical status, need for invasive ventilation and effects on weaning. RESULTS: We included a total of seven studies, five being randomized controlled trials (RCTs, population range 44-92 patients). The two small prospective studies (n = 10 and n = 11) did not have a control group. Four studies focused on adults, and three enrolled a pediatric population. We found a large heterogeneity regarding sample size, age and gender distribution, inclusion criteria (different severity scores, if any) and ketamine dosing (bolus and/or continuous infusion). Of the five RCTs, three compared ketamine to placebo, while one used fentanyl and the other aminophylline. The outcomes evaluated by the included studies were highly variable. Despite paucity of data and large heterogeneity, an overview of the included studies suggests absence of clear benefit produced by ketamine in patients with refractory SAE, and some signals towards side effects. CONCLUSION: Our systematic review does not support the use of ketamine in refractory SAE. A limited number of prospective studies with large heterogeneity was found. Well-designed multicenter RCTs are desirable.

A single dose of aminophylline administration during therapeutic hypothermia; does it make a difference in glomerular filtration rate?

Aminophylline has been demonstrated to be effective in improving renal functions of the infants suffering from acute kidney injury (AKI) due to perinatal asphyxia. We aimed to evaluate the effect of a single-dose aminophylline on estimated glomerular filtration rate (eGFR), urine output (UO), and incidence and severity of AKI according to the pediatric-modified RIFLE and neonatal RIFLE criteria in newborns with perinatal asphyxia under therapeutic hypothermia. This was a single-center, retrospective cohort study including newborns (gestational age ≥36 weeks) who underwent therapeutic hypothermia due to hypoxic ischemic encephalopathy between 2016 and 2019. Demographic and clinical data were obtained from electronic medical records and patient files. Two patient groups were established: aminophylline group and control group which were only under therapeutic hypothermia. Twenty-one newborns were in the aminophylline group and 13 newborns were in the control group. Our study revealed that on the third day of life (DOL), eGFR was significantly higher in the control group (p=0.025), but UO was significantly higher in the aminophylline group (p=0.021). In the aminophylline group, eGFR on the first DOL was higher than the value on the second DOL (p=0.017) while UO was higher on the second and third DOL compared to the first DOL (1-2 DOL p=0.006, and 1-3 DOL p=0.004). However, in the control group, there was no statistically significant difference in UO over the four DOL. Both groups were similar in the presence, severity, and outcome of AKI.Conclusion: This study demonstrated that aminophylline increases UO even in the infants under therapeutic hypothermia. However, the eGFR did not significantly increase in the aminophylline group. Understanding how therapeutic hypothermia affects pharmacokinetics may help us improve our results in future studies. What is known: • Therapeutic hypothermia (TH) reduces the incidence of acute kidney injury in asphyxiated newborns. • Aminophylline is effective in improving renal functions in asphyxiated newborns. What is new: • This is the first study evaluating the effect of a single dose of aminophylline on renal functions in newborns under TH. • A single dose of aminophylline administration in newborns under TH was associated with increased urine output especially on the third day of life. However, no significant increase was detected in glomerular filtration rate associated with aminophylline administration.

The effect of preoperative aminophylline on the recovery profile after major pelvic-abdominal surgeries: a randomized controlled double-blinded study.

BACKGROUND: This study compared the effects of premedication with different doses of aminophylline on the recovery profile after general anaesthesia. METHODS: Forty-five patients scheduled for pelvic-abdominal surgeries were divided into 3 groups: Group C: the patients received 100 ml of IV normal saline, Group A1: the patients received 2 mg/kg IV aminophylline, and Group A2: the patients received 4 mg/kg IV aminophylline 30 min before induction of general anaesthesia. The following data were recorded: demographic data, ASA physical status, duration of anaesthesia and surgery, heart rate, mean arterial blood pressure, propofol dose, fentanyl dose, times to reach BIS (48 ± 2) after induction of anaesthesia and to reach a value of 80 after discontinuation of sevoflurane anaesthesia, time to recovery of consciousness and to tracheal extubation and to discharge from the post-anaesthesia care unit, and side effects of aminophylline. RESULTS: The time to reach a BIS of 48 ± 2 was significantly lower for the control group than group A2 (70.67 ± 22.50 and 106.67 ± 34.77 s for groups C and A2, respectively, p -value =0.01). The time to reach a BIS of 80 was significantly longer for the control group than group A1 andA2 (5.6 ± 1.40,3.5 ± 1.93and 2.53 ± 1.72 min for groups C,A1 and A2, respectively, p -value < 0.01). The time to ROC was significantly longer for the control group than groups A1 and A2 (8.93 ± 0.92, 5.6 ± 2.47 and 4.53 ± 3.33 min for groups C, A1 and A2, respectively; p -value < 0.01). The extubation time was significantly longer for the control group than groups A1 and A2 (12.4 ± 1.08, 7.87 ± 3.27 and 6.6 ± 2.47 min for groups C, A1 and A2, respectively; p -value < 0.01). CONCLUSION: Premedication with aminophylline enhanced the recovery profile after pelvic-abdominal surgeries under general anaesthesia without cardiovascular complications. CLINICAL TRIAL REGISTRATION: Name of the registry: Register@ClinicalTrials.gov Trial registration number: ClinicalTrials.gov Identifier: NCT04151381. Date of registration, November 5, 2019, 'Retrospectively registered'.

The beneficial effect of glycerophosphocholine to local fat accumulation: a comparative study with phosphatidylcholine and aminophylline.

Injection lipolysis or mesotherapy gained popularity for local fat dissolve as an alternative to surgical liposuction. Phosphatidylcholine (PPC) and aminophylline (AMPL) are commonly used compounds for mesotherapy, but their efficacy and safety as lipolytic agents have been controversial. Glycerophosphocholine (GPC) is a choline precursor structurally similar to PPC, and thus introduced in aesthetics as an alternative for PPC. This study aimed to evaluate the effects of GPC on adipocytes differentiation and lipolysis and compared those effects with PPC and AMPL using in vitro and in vivo models. Adipogenesis in 3T3-L1 was measured by Oil Red O staining. Lipolysis was assessed by measuring the amount of glycerol released in the culture media. To evaluate the lipolytic activity of GPC on a physiological condition, GPC was subcutaneously injected to one side of inguinal fat pads for 3 days. Lipolytic activity of GPC was assessed by hematoxylin and eosin staining in adipose tissue. GPC significantly suppressed adipocyte differentiation of 3T3-L1 in a concentration-dependent manner (22.3% inhibition at 4 mM of GPC compared to control). Moreover, when lipolysis was assessed by glycerol release in 3T3-L1 adipocytes, 6 mM of GPC stimulated glycerol release by two-fold over control. Subcutaneous injection of GPC into the inguinal fat pad of mice significantly reduced the mass of fat pad and the size of adipocytes of injected site, and these effects of GPC were more prominent over PPC and AMPL. Taken together, these results suggest that GPC is the potential therapeutic agent as a local fat reducer.

Peri-transplant aminophylline in pediatric kidney transplant recipients of donation after brain death: a double-blinded placebo-controlled randomized clinical trial.

BACKGROUND: During kidney transplantation, the transplanted kidney undergoes ischemia reperfusion injury, with adenosine being a major mediator. This study aimed to assess whether aminophylline, an adenosine receptor antagonist, improves early graft function and reduces incidence of delayed graft function (DGF) and slow graft function (SGF). METHODS: Single center, double-blinded, placebo-controlled randomized clinical trial. Pediatric patients admitted for renal transplantation from donation after brain death donors were randomized into a treatment arm receiving aminophylline and a placebo arm receiving normal saline infusions. Primary outcome was estimated glomerular filtration rate (eGFR) at 5 days post-transplant. Secondary outcomes were rates of DGF/SGF and urinary neutrophil gelatinase-associated lipocalin (NGAL) levels. RESULTS: Twenty-three patients were randomized to aminophylline and 27 to placebo. There was no difference in day 5 eGFR, rate of DGF/SGF, or urine NGAL/Creatinine level between aminophylline vs. placebo arm (eGFR 67.39 ± 38.9 ml/min/1.73m2 vs. 80.48 ± 52.1 ml/min/1.73m2p = 0.32; DGF/SGF 5/23 (21.7%) vs. 3/27 (11.1%) p = 0.31; urine NGAL/creatinine 300.5 ng/mg IQR 105.5-1464.5 ng/mg vs. 425.4 ng/mg IQR 140.3-1126.2 ng/mg, p = 0.95; respectively). At 12 months, there was 100% patient survival and 98% graft survival. eGFR at 12 months was similar between the two arms. CONCLUSIONS: There was no benefit in peri-transplant aminophylline administration. Our results are limited by small sample size, since sample calculations were based on primary outcome of day 5 eGFR and low rate of DGF/SGF, which may have precluded us from demonstrating efficacy. Further clinical studies are necessary to determine any benefit of aminophylline in kidney transplant recipients, particularly from high-risk donors.

Immunological outcomes in infants with ROP after dexamethasone and aminophylline.

This research aims to improve anaesthesia services given to preterm infants by the use of dexamethasone and aminophylline administrated under sevoflurane, and to analyze its effect on the cell-mediated immunity (CD4+CD25+Foxp3+(T-reg) and CD4+CD25highFoxp3+CD127low). We have examined 74 premature babies with retinopathy of prematurity (ROP) at the 3-5 stages during the 25-32 week gestation period (1-6 months after birth). Both immunomodulators had no significant effect on clinical parameters after one dose (P > .05). Aminophylline (2.4% solution, 0.1 mL/kg or 0.132 mL per infant on average) and dexamethasone (0.4% solution, 0.1 mg/kg or 0.132 mL per infant on average) were intravenously injected 15 minutes before the end of the surgery. Required anaesthesia depth was maintained with inhalation anaesthetic (1.5-2.0 IAC), and the minimum fresh gas flow was not less than 2 L. Blood samples were taken from the vein (anaesthesia induction stage) into the tubes containing EDTA (the anticoagulant), stored at 20-25°C, and then, processed and stained within 24 hours after sampling. Both immunomodulators had no significant effect on clinical parameters after one dose (P > .05). Short-term shift in regulatory T-cell level affected by dexamethasone has a negative effect combined with further withdrawal effect that this hormonal drug has. Aminophylline has such clinical effects as improving pulmonary ventilation, decrease in apnoea frequency, and improving blood gas indices. Aminophylline has less expressed but more prolonged positive effect during the day when used for several days. It may lead to a persistent positive effect with progressive treatment outcomes.

Aminophylline promotes mitochondrial biogenesis in human pulmonary bronchial epithelial cells.

Recently, mitochondrial dysfunction has been linked to the development of common airway disorders, such as chronic obstructive pulmonary disease (COPD) and asthma. Phosphodiesterase inhibitors are therapeutic agents for various diseases. Aminophylline is a nonselective phosphodiesterase inhibitor used to treat common lung diseases. In this study, we show that aminophylline promotes mitochondrial biogenesis in cultured human pulmonary bronchial epithelial cells (HPBECs). Aminophylline treatment induces the expression of transcriptional coactivator PGC-1α and transcriptional factors NRF1 and TFAM. The effect of aminophylline on mitochondrial biogenesis can be revealed by its promotion of the ratio of mitochondrial DNA to nuclear DNA (mtDNA/nDNA), mitochondrial protein cytochrome B and mitochondrial mass. At the cellular level, aminophylline increases the mitochondrial respiration rate and ATP production but reduces oxygen content. Consistently, we show that aminophylline activates the CREB-PGC-1α signaling pathway to promote mitochondrial biogenesis. The inhibition of CREB activation by its specific inhibitor H89 obscures the induction of PGC-1α, NRF1, and TFAM by aminophylline, and also abolishes the action of aminophylline on the mtDNA/nDNA ratio and respiration rate, suggesting that the activation of CREB is required for the action of aminophylline. Collectively, our study supports that aminophylline is a potent metabolic inducer of mitochondrial biogenesis in epithelial cells. Aminophylline could have a therapeutic effect on epithelial mitochondrial function in lung diseases.

Aminophylline increases parasternal muscle action in awake canines.

The traditional theophylline bronchodilator, aminophylline, is still widely used, especially in the treatment of COPD. The effects of aminophylline on ventilation and action of the costal diaphragm have been previously defined, but other respiratory muscles - notably the chest wall, are not well determined. Therefore, we investigated the effects of aminophylline on the Parasternal intercostal, a key obligatory inspiratory muscle, examining muscle length, shortening and EMG. We studied 11 awake canines, chronically implanted with sonomicrometer crystals and fine-wire EMG electrodes in the parasternal muscle. Ventilatory parameters, muscle length (shortening), and moving average muscle EMG activity, were measured at baseline and with aminophylline, during resting and hypercapnic stimulated breathing. Experiments were carried out prior to administration of aminophylline (baseline), and 1.5 h after loading and ongoing infusion. Minute ventilation, tidal volume and respiratory frequency all increased significantly with aminophylline, both during resting breathing and at equivalent levels of hypercapnic stimulated breathing. Parasternal baseline muscle length was entirely unchanged with aminophylline. Parasternal shortening increased significantly with aminophylline while corresponding parasternal EMG activity remained constant, consistent with increased contractility. Thus, in awake, intact mammals, aminophylline, in the usual therapeutic range, elicits increased ventilation and increased contractility of all primary inspiratory respiratory muscles, including both chest wall and diaphragm.

Effects of aminophylline on airway epithelial-mesenchymal transition in brown Norway rats after repeated allergen challenge.

Purpose: Chronic asthma is characterized by airway inflammation and remodeling. The aim of this study is to evaluate the effects of aminophylline on airway epithelial-mesenchymal transition (EMT). Materials and methods: Two experimental groups of brown Norway rats that were repeatedly challenged with aerosolized ovalbumin (OA) were given oral aminophylline (OA-aminophylline group) or saline only (OA-saline group). A third group was challenged by saline as a control. The rats were anesthetized and pulmonary function were performed. Immuno-histochemical staining of epithelial markers (zonula occludens-1 (ZO-1)) and mesenchymal markers (vimentin) in the airway were performed. The protein expressions of ZO-1, E-cadherin, vimentin, fibronectine, TGF-ß1, SMAD 2/3, JNK, and p38 MAPK were examined by western blot. Results: Aminophylline had beneficial effects on airway inflammation, and airway remodeling in the OA-aminophylline group compared to the OA-saline group. The OA-saline group had decreased ZO-1 but increased vimentin according to immuno-histochemical staining. The protein expression indicated decreases in ZO-1 and E-cadherin but increases in vimentin, fibronectine, TGF-ß1, SMAD 2/3, JNK, and p38 MAPK in comparison to the other two groups. The OA-aminophylline group had higher ZO-1 but lower vimentin in immuno-histochemical staining compared to the OA-saline group. The protein expression showed higher ZO-1 and E-cadherin but lower vimentin, fibronectine, TGF-ß1, SMAD 2/3, JNK, and p38 MAPK when compared to the OA-saline group. Conclusions: Ovalbumin increases airway remodeling and airway EMT. Aminophylline is effective in preventing airway remodeling and airway EMT in Brown Norway rats after repeated allergen challenge.

Protective effects of Gαq-RGS2 signalling inhibitor in aminophylline induced cardiac arrhythmia.

An over activation of GPCR mediated Gαq dependent signalling pathway is widely associated with the development of cardiovascular abnormalities. The objective of study was to evaluate the effects of (1-(5-chloro-2-hydroxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one) Gαq-RGS2 signalling inhibitor on aminophylline induced cardiac arrhythmia in rats. Rats were divided into four groups; normal rats, disease control (DC, aminophylline treated 100 mg/kg/d, i.p., 7 days), Gαq-RGS2 signalling inhibitor (1 and 10 mg/kg/d, p.o., 7 days) treated arrhythmic rats. Gαq-RGS2 signalling inhibitor was administered 1 hour prior to the administration of aminophylline from 1st day. At the end of study, heart rate (HR), QRS complex, QT and RR interval were measured by electrocardiogram (ECG) of anesthetized rats. Systolic and diastolic blood pressure (SBP, DBP) by invasive method, cardiac damage markers (CK-MB, LDH) in the serum, antioxidant enzymes (SOD, catalase, glutathione) and cAMP level were measured. The treatment of Gαq-RGS2 signalling inhibitor (10 mg/kg) significantly abolished the aminophylline induced increase of heart rate, prolongation of RR and QT interval as compared to DC rats. Gαq-RGS2 signalling inhibitor (1 and 10 mg/kg) significantly attenuated the prolongation in QRS complex, increase of SBP, DBP and cardiac damage markers as compared to DC. Gαq-RGS2 signalling inhibitor treatment (10 mg/kg) significantly reduced the cAMP level and increased the antioxidant enzyme level as compared to DC. Gαq-RGS2 signalling inhibitor (10 mg/kg) showed the protective effect against the aminophylline induced cardiac arrhythmia and it might be due to improvement in cAMP level and antioxidant enzymes.