Best step-up treatments for children with uncontrolled asthma: a systematic review and network meta-analysis of individual participant data.

BACKGROUND: There is uncertainty about the best treatment option for children/adolescents with uncontrolled asthma despite inhaled corticosteroids (ICS) and international guidelines make different recommendations. We evaluated the pharmacological treatments to reduce asthma exacerbations and symptoms in uncontrolled patients age <18 years on ICS. METHODS: We searched MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Embase, Web of Science, National Institute for Health and Care Excellence Technology Appraisals, National Institute for Health and Care Research Health Technology Assessment series, World Health Organization International Clinical Trials Registry, conference abstracts and internal clinical trial registers (1 July 2014 to 5 May 2023) for randomised controlled trials of participants age <18 years with uncontrolled asthma on any ICS dose alone at screening. Studies before July 2014 were retrieved from previous systematic reviews/contact with authors. Patients had to be randomised to any dose of ICS alone or combined with long-acting ß2-agonists (LABA) or combined with leukotriene receptor antagonists (LTRA), LTRA alone, theophylline or placebo. Primary outcomes were exacerbation and asthma control. The interventions evaluated were ICS (low/medium/high dose), ICS+LABA, ICS+LTRA, LTRA alone, theophylline and placebo. RESULTS: Of the 4708 publications identified, 144 trials were eligible. Individual participant data were obtained from 29 trials and aggregate data were obtained from 19 trials. Compared with ICS Low, ICS Medium+LABA was associated with the lowest odds of exacerbation (OR 0.44, 95% credibility interval (95% CrI) 0.19-0.90) and with an increased forced expiratory volume in 1 s (mean difference 0.71, 95% CrI 0.35-1.06). Treatment with LTRA was the least preferred. No apparent differences were found for asthma control. CONCLUSIONS: Uncontrolled children/adolescents on low-dose ICS should be recommended a change to medium-dose ICS+LABA to reduce the risk for exacerbation and improve lung function.

Caffeine versus other methylxanthines for the prevention and treatment of apnea in preterm infants.

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.

Glutathione-Mediated Neuroprotective Effect of Purine Derivatives.

Numerous basic studies have reported on the neuroprotective properties of several purine derivatives such as caffeine and uric acid (UA). Epidemiological studies have also shown the inverse association of appropriate caffeine intake or serum urate levels with neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson's disease (PD). The well-established neuroprotective mechanisms of caffeine and UA involve adenosine A2A receptor antagonism and antioxidant activity, respectively. Our recent study found that another purine derivative, paraxanthine, has neuroprotective effects similar to those of caffeine and UA. These purine derivatives can promote neuronal cysteine uptake through excitatory amino acid carrier protein 1 (EAAC1) to increase neuronal glutathione (GSH) levels in the brain. This review summarizes the GSH-mediated neuroprotective effects of purine derivatives. Considering the fact that GSH depletion is a manifestation in the brains of AD and PD patients, administration of purine derivatives may be a new therapeutic approach to prevent or delay the onset of these neurodegenerative diseases.

Theophylline for the management of respiratory disorders in adults in the 21st century: A scoping review from the American College of Clinical Pharmacy Pulmonary Practice and Research Network.

Theophylline is an oral methylxanthine bronchodilator recommended as alternate therapy for the treatment of asthma and chronic obstructive pulmonary disease (COPD). However, it is not generally recommended for the treatment of other respiratory disorders such as obstructive sleep apnea (OSA) or hypoxia. Most clinical practice guidelines rely on evidence published prior to the year 2000 to make these recommendations. This scoping review aimed to gather and characterize evidence describing theophylline for the management of respiratory disorders in adults between January 1, 2000 and December 31, 2020. Databases searched included Ovid MEDLINE, Embase, CINAHL Complete, Scopus, and International Pharmaceutical Abstracts. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. Studies were included if they were published in English, theophylline was used for any respiratory disorder, and the study outcomes were disease- or patient-oriented. After removal of duplicates, 841 studies were screened and 55 studies were included. Results aligned with current clinical guideline recommendations relegating theophylline as an alternative therapy for the treatment of respiratory disorders, in favor of inhaled corticosteroids and inhaled bronchodilators. This scoping review identified the need for future research including: theophylline versus other medications deemed alternative therapies for asthma and COPD, meta-analyses of low-dose theophylline, and studies evaluating evidence-based patient-oriented outcomes for OSA, hypoxia, ventilator-induced diaphragmatic dysfunction, and spinal cord injury-related pulmonary function.

Theophylline for Spinal Cord Injury Associated Bradycardia.

Background: Spinal cord injury (SCI) related bradycardia occurs frequently in patients with high cervical spine injuries. In patients with SCI-related symptomatic bradycardia, a variety of agents have been used to improve heart rate and reduce the need for vasopressor therapy. The literature concerning the use of theophylline in this disease state is sparse. Objective: The primary objective of this study was to evaluate and describe the use of theophylline for SCI-related symptomatic bradycardia. Methods: This was a retrospective case series of patients with SCI-related symptomatic bradycardia who were treated with theophylline. Patients were evaluated based on clinical response to theophylline. Patients were classified as a responder if vasopressors were discontinued or the number of bradycardia episodes decreased following the initiation of theophylline. Results: A total of twenty-six patients were included in the study. 17 (65.4%) patients were classified as responders, 5 (19.2%) patients were classified as non-responders, and 4 (15.4%) of patients were classified as undetermined. 11 patients (43.31%) were discharged on theophylline with 7 of these patients (41.2%) classified as responders. There were no significant differences between those classified as responders and those who were not. Conclusion and Relevance: This case series suggest that theophylline could be used as adjunctive therapy in patients with bradycardia secondary to acute SCI who achieve an adequate response to theophylline.

Survey the effect of drug treatment on modulation of cytokines gene expression in allergic rhinitis.

Allergic rhinitis as common airway disease has high prevalence in all peoples worldwide. In allergic diseases, Th2 cells release type 2 cytokines that support the inflammation in airways. All the drugs used for allergic rhinitis do not cure completely, and the choice of drugs according to cost and efficacy is very important in all groups of atopic patients. Therefore, in this study, the effect of commercial drugs on cytokine gene expression has been studied. Male Balb/c mice were divided into six groups. Allergic rhinitis was induced in five of the six groups with ovalbumin, and four of these five groups were treated with salbutamol, budesonide, theophylline, and montelukast. The fifth group was used as positive control group and the sixth group as negative control group. For the survey, RNA was extracted, cDNA was synthesized, and quantitative real-time PCR was done for 21 genes. The four drugs had different effects on mRNA expression of cytokines (IL-1b, 2, 4, 5, 7, 8, 9, 11, 12, 13, 17, 18, 22, 25, 31, 33, 37, IFN-γ, TNF-α, TGF-ß1, and eotaxin) in the allergic rhinitis groups. Salbutamol can be used during pregnancy and breastfeeding, but it has some side effects. Budesonide in the inhaled form is generally safe in pregnancy. Theophylline cannot control allergic attack in the long run. Montelukast is not useful in the treatment of acute allergic attacks. Immunomodulatory and anti-inflammatory effects of drugs in control of allergic rhinitis via Th2 cytokines can be new approaches in molecular medicine.

Clinical pharmacokinetics of terbutaline in humans: a systematic review.

Terbutaline is used for the management of bronchospasm associated with asthma, bronchitis, emphysema, and chronic obstructive pulmonary disease. A systematic review would be beneficial to assess the impact of routes of administration, stereoisomerism, disease states, smoking, age, exercise, and chronobiology on pharmacokinetics (PK) of terbutaline in humans. PubMed and Google Scholar databases were searched to screen all the relevant articles consisting of at least one of the PK parameters after administration of oral, inhaled, and intravenous (IV) terbutaline in humans. Oral studies of terbutaline depicted a linear relationship between plasma concentration (Cp) and the administered dose. The IV studies demonstrated multi-exponential behavior for disposition and renal clearance. Higher systemic availability was observed with inhaled as compared to oral route, and chrono-pharmacokinetic behavior was notable. Time to reach maximum plasma concentration (Tmax) was prolonged, and maximum plasma concentration (Cmax) was lowered after exercise. The primary route of excretion in chronic kidney disease (CKD) patients is reported to be nonrenal. In pregnant women, the Cp of terbutaline is lowered and clearance is increased. The addition of theophylline to terbutaline did not affect the PK of terbutaline; hence, both can be used without dose adjustment. This review summarizes all the available PK parameters of terbutaline, and it may be helpful for researchers in the development and evaluation of PK models as well as in designing optimal dosage regimens in different clinical conditions.

Characteristics of medicine use for children with asthma in China: a nationwide population-based study.

OBJECTIVE: To analyze the asthma medication use in Chinese children of different age groups, regions, and levels of cities in China, based on the 2015 Healthcare Insurance Data in China. METHODS: The China Healthcare Insurance Research Association (CHIRA) database was searched for children from 0 to 14 years old diagnosed as asthma based on the "J45" and "J46" coded in ICD-10. A cross-sectional study design was employed. RESULTS: A total of 308,550 children were identified, all of whom were treated under the coverage of healthcare insurance. Among them, 2,468 children were eligible for inclusion in the present study. Compared with the current status of asthma care in European and American countries, under the guidelines for the diagnosis and treatment of asthma in China, the use percentages of ICS and short-acting ß2 receptor agonist in children with asthma in China were lower, but the use percentages of oral corticosteroids, long-acting ß2 receptor agonist, and theophylline (especially intravenous theophylline) were higher, especially in the Central and West China. CONCLUSION: The asthma medication use was attributed to many factors, thus efforts are still needed to further popularize the GINA programs and China's guidelines for asthma diagnosis and treatment, especially in the Central and West China.

The characteristics and costs of severe theophylline toxicity in a tertiary critical care unit in Eastern Cape Province, South Africa.

BACKGROUND: Severe theophylline toxicity requiring haemodialysis accounts for approximately one-third of drug toxicity cases admitted to the Livingstone Tertiary Hospital (LTH) intensive care unit (ICU) in Gqeberha, South Africa, imposing a significant resource burden. OBJECTIVES: To investigate the characteristics and burden of severe theophylline toxicity in an Eastern Cape Province tertiary hospital adult ICU. METHODS: A retrospective review of all severe theophylline toxicity admissions to the ICU from 1 January 2013 to 31 December 2018 was conducted. Demographic and clinical data were captured and analysed. The National Department of Health 2019 fees schedule was used to calculate costs based on duration of ICU stay and number of haemodialysis sessions received. RESULTS: Of the 57 patients included in the study, 84% were cases of deliberate self-harm. The majority were aged <40 years (77%) and female (79%). The mean (standard deviation (SD)) initial serum theophylline level was 612 (269) µmol/L. Complications included convulsions (n=12; 21%), arrhythmias (n=9; 16%), need for mechanical ventilation (n=7; 12%) and death (n=4; 7%). The main risk factors for these complications were age ≥30 years, an inappropriately normal or elevated initial serum potassium level, an elevated serum creatinine kinase level and an elevated initial serum theophylline level. Receiver operator characteristic curve analysis assessing the initial serum theophylline level as a discriminator for life-threatening complications produced an area under the curve of 0.71 for serum theophylline >400 µmol/L (sensitivity 88%, specificity 12%). All the 4 patients who died had an initial serum theophylline level >1 000 µmol/L. The mean (SD) cost per admission amounted to ZAR16 897 (10 718), with a mean of one 4-hour dialysis session per admission. CONCLUSION: Severe theophylline toxicity, usually in the context of  deliberate self-harm, is a preventable yet life-threatening toxicity encountered at  LTH.  Demographic  risk factors include young females from certain areas in and around Gqeberha.  Risk factors for complications include older age, paradoxically normal or elevated serum potassium levels, elevated serum creatinine kinase levels and an initial serum theophylline level >400 µmol/L. Patients with these clinical features should be closely monitored and treated timeously at an appropriate level of care. The need for ICU admission and dialysis, both limited resources, makes the treatment of severe theophylline toxicity costly. Further studies of the underlying psychosocial drivers, local prescribing practices and preventive interventions related to severe theophylline toxicity are required.

Antihyperlipidemic effect and increased antioxidant enzyme levels of aqueous extracts from Liupao tea and green tea in vivo.

Liupao tea (fermented dark tea) may improve the active function of hyperlipidemia. Utilizing a hyperlipidemia Sprague-Dawley model and UPLC-MS/MS metabolomics, we examined how the effect of Liupao and green tea extracts on hyperlipidemia and antoxidant enzyme levels and compared their constituents. The results showed that the two types of tea could reduce the levels of total cholesterol (TC), total triglyceride, and low-density lipoprotein cholesterol (LDL-C); increase the contents of bile acids and cholesterol in feces; and improve catalase and glutathione peroxidase (GSH-Px) activities. Compared with the model control group, Liupao tea effectively reduced TC and LDL-C levels by 39.53% and 58.55% and increased GSH-Px activity in the liver by 67.07%, which was better than the effect of green tea. A total of 93 compounds were identified from two samples; the amounts of alkaloids and fatty acids increased compared with green tea, and ellagic acid, hypoxanthine, and theophylline with relatively high contents in Liupao tea had a significantly positive correlation with antihyperlipidemic and antioxidant effects. Therefore, Liupao tea had better antihyperlipidemic and antioxidant activities in vivo than green tea, which might be related to the relatively high content of some active substances.

Efficacy and Safety of Saline Nasal Irrigation Plus Theophylline for Treatment of COVID-19-Related Olfactory Dysfunction: The SCENT2 Phase 2 Randomized Clinical Trial.

Importance: Recent studies suggest that theophylline added to saline nasal irrigation (SNI) can be an effective treatment for postviral olfactory dysfunction (OD), a growing public health concern during the COVID-19 pandemic. Objective: To evaluate the efficacy and safety of theophylline added to SNI compared with placebo for COVID-19-related OD. Design, Setting, and Participants: This triple-blinded, placebo-controlled, phase 2 randomized clinical trial was conducted virtually between March 15 and August 31, 2021. Adults residing in Missouri or Illinois were recruited during this time period if they had OD persisting for 3 to 12 months following suspected COVID-19 infection. Data analysis was conducted from October to December 2021. Interventions: Saline sinus rinse kits and bottles of identical-appearing capsules with either 400 mg of theophylline (treatment) or 500 mg of lactose powder (control) were mailed to consenting study participants. Participants were instructed to dissolve the capsule contents into the saline rinse and use the solution to irrigate their nasal cavities in the morning and at night for 6 weeks. Main Outcomes and Measures: The primary outcome was the difference in the rate of responders between the treatment and the control arms, defined as a response of at least slightly better improvement in the Clinical Global Impression-Improvement scale posttreatment. Secondary outcome measures included changes in the University of Pennsylvania Smell Identification Test (UPSIT), the Questionnaire for Olfactory Disorders, the 36-Item Short Form Health Survey on general health, and COVID-19-related questions. Results: A total of 51 participants were enrolled in the study; the mean (SD) age was 46.0 (13.1) years, and 36 (71%) participants were women. Participants were randomized to SNI with theophylline (n = 26) or to SNI with placebo (n = 25). Forty-five participants completed the study. At the end of treatment, 13 (59%) participants in the theophylline arm reported at least slight improvement in the Clinical Global Impression-Improvement scale (responders) compared with 10 (43%) in the placebo arm (absolute difference, 15.6%; 95% CI, -13.2% to 44.5%). The median difference for the UPSIT change between baseline and 6 weeks was 3.0 (95% CI, -1.0 to 7.0) for participants in the theophylline arm and 0.0 (95% CI, -2.0 to 6.0) for participants in the placebo arm. Mixed-model analysis revealed that the change in UPSIT scores through study assessments was not statistically significantly different between the 2 study arms. Eleven (50%) participants in the theophylline arm and 6 (26%) in the placebo arm had a change of 4 or more points in UPSIT scores from baseline to 6 weeks. The difference in the rate of responders as measured by the UPSIT was 24% (95% CI, -4% to 52%) in favor of theophylline. Conclusions and Relevance: This randomized clinical trial suggests that the clinical benefit of theophylline nasal irrigations on olfaction in participants with COVID-19-related OD is inconclusive, though suggested by subjective assessments. Larger studies are warranted to investigate the efficacy of this treatment more fully. Trial Registration: ClinicalTrials.gov Identifier: NCT04789499.

Profound Perturbation in the Metabolome of a Canine Obesity and Metabolic Disorder Model.

Canine models are increasingly being used in metabolic studies due to their physiological similarity with humans. The present study aimed to identify changes in metabolic pathways and biomarkers with potential clinical utility in a canine model of obesity and metabolic disorders induced by a high-fat diet (HFD). Eighteen male beagles were included in this study, 9 of which were fed a HFD for 24 weeks, and the remaining 9 were fed normal chow (NC) during the same period. Plasma and urine samples were collected at weeks 12 and 24 for untargeted metabolomic analysis. Dogs fed a HFD showed a gradual body weight increase during the feeding period and had hyperlipidemia, increased leukocyte counts, and impaired insulin sensitivity at week 24. Plasma and urine metabonomics analysis displayed clear separations between the HFD-fed and NC-fed dogs. A total of 263 plasma metabolites varied between the two groups, including stearidonic acid, linolenic acid, carnitine, long-chain ceramide, 3-methylxanthine, and theophylline, which are mainly engaged in fatty acid metabolism, sphingolipid metabolism, and caffeine metabolism. A total of 132 urine metabolites related to HFD-induced obesity and metabolic disorders were identified, including 3-methylxanthine, theophylline, pyridoxal 5'-phosphate, and harmine, which participate in pathways such as caffeine metabolism and vitamin digestion and absorption. Eight metabolites with increased abundance (e.g., 3-methylxanthine, theophylline, and harmine) and 4 metabolites with decreased abundance (e.g., trigonelline) in both the plasma and urine of the HFD-fed dogs were identified. In conclusion, the metabolomic analysis revealed molecular events underlying a canine HFD model and identified several metabolites as potential targets for the prevention and treatment of obesity-related metabolic disorders.

Oral theophylline augmentation for patients with missed or inadequate seizures with electroconvulsive therapy.

AIM: An inadequate seizure occasionally occurs during a course of acute electroconvulsive therapy (ECT) under the maximum approved electrical stimulation in Japan of 504 mC. This retrospective study was conducted to determine the effectiveness and adverse reactions of an oral theophylline augmentation technique. METHODS: A retrospective review of medical records was conducted of patients admitted to the Department of Psychiatry, Hiroshima Citizens Hospital, who received acute phase ECT from October 2014 to March 2017. RESULTS: A theophylline augmentation technique was instituted in 13 patients (7 males, 6 females; 56-79 years old). The total number of ECT sessions per patient ranged from 9 to 20 and the number of those with theophylline augmentation per patient ranged from 1 to 17. An augmentation effect was noted in all patients and each finished the scheduled ECT course, except for 1 who developed memory disturbance. The maximum dose of theophylline ranged from 200 to 700 mg/day, and the serum level at 06:00 on the day of the ECT session ranged from 5.3 to 23.6 mg/L in 12 patients, as 1 missed the examination. CONCLUSION: Oral theophylline augmentation can be considered as an effective treatment option for patients undergoing ECT with inadequate seizures.

Theophylline: Old Drug in a New Light, Application in COVID-19 through Computational Studies.

Theophylline (3-methyxanthine) is a historically prominent drug used to treat respiratory diseases, alone or in combination with other drugs. The rapid onset of the COVID-19 pandemic urged the development of effective pharmacological treatments to directly attack the development of new variants of the SARS-CoV-2 virus and possess a therapeutical battery of compounds that could improve the current management of the disease worldwide. In this context, theophylline, through bronchodilatory, immunomodulatory, and potentially antiviral mechanisms, is an interesting proposal as an adjuvant in the treatment of COVID-19 patients. Nevertheless, it is essential to understand how this compound could behave against such a disease, not only at a pharmacodynamic but also at a pharmacokinetic level. In this sense, the quickest approach in drug discovery is through different computational methods, either from network pharmacology or from quantitative systems pharmacology approaches. In the present review, we explore the possibility of using theophylline in the treatment of COVID-19 patients since it seems to be a relevant candidate by aiming at several immunological targets involved in the pathophysiology of the disease. Theophylline down-regulates the inflammatory processes activated by SARS-CoV-2 through various mechanisms, and herein, they are discussed by reviewing computational simulation studies and their different applications and effects.

Therapeutic diminution of Interleukin-10 with intranasal theophylline administration in hyposmic patients.

OBJECTIVE: To determine changes in nasal mucus Interleukin-10 (IL-10) before and after intranasal theophylline treatment in hyposmic patients, and the relationship of these changes to orally administered theophylline treatment. DESIGN: IL-10 was measured in nasal mucus samples of 17 normal subjects and 39 patients with hyposmia of multiple etiologies by use of a sensitive spectrophotometric ELISA assay. Hyposmia is defined clinically by standardized evaluation of impaired olfactometry, as well as subjectively self reported by the patient. RESULTS: Prior to treatment, IL-10 levels in nasal mucus were increased in hyposmic patients compared to controls. Following intranasal theophylline administration, over half of treated patients experienced a decrease of nasal mucus IL-10 toward control levels, correlated with a significant improvement in taste and smell function. Patients who increased with intranasal administration, similar to previously reported oral administration, showed no significant improvement in taste or smell function. CONCLUSIONS: Nasal mucus IL-10 decreased in patients treated with intranasal theophylline. Mechanisms of action include phosphodiesterase and nuclear factor kappa-B inhibition, correlated with an improvement in both olfaction and gustation. IL-10 is induced by therapeutic and systemic administration of theophylline as with oral dosage, but reduced by lower and localized treatment.

Smell Changes and Efficacy of Nasal Theophylline (SCENT) irrigation: A randomized controlled trial for treatment of post-viral olfactory dysfunction.

OBJECTIVE: To evaluate the efficacy and safety of intranasal theophylline saline irrigation on olfactory recovery in patients with post-viral olfactory dysfunction (PVOD). METHODS: Between May 2019 and April 2020, we conducted a double-blinded, placebo-controlled randomized clinical trial of adults with 6-36 months of PVOD. Patients were randomized to nasal theophylline saline irrigation or placebo saline irrigation twice a day for 6 weeks. The primary outcome was the Global Rating of Smell Change. Secondary outcomes were changes in the University of Pennsylvania Smell Identification Test (UPSIT) and Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS). RESULTS: Twenty-two patients (n = 12, theophylline; n = 10, placebo) completed the study. Slightly more patients in the theophylline group (33%) reported improved smell compared to the placebo group (30%, difference 3.3%, 95% CI -35.6% to 42.3%). The median differences in pre- and post-treatment UPSIT and QOD-NS change between the two groups were 1 (95% CI -3 to 5) and -10 (95% CI -15 to -4), respectively in favor of theophylline. Three patients receiving theophylline and 2 receiving placebo had clinically meaningful improvements on the UPSIT (difference 5%, 95% CI -30% to 40%). There were no adverse events, and serum theophylline levels were undetectable in 10/10 patients. CONCLUSIONS: While safe, there were no clinically meaningful differences in olfactory change between the two groups except for olfaction-related quality of life, which was better with theophylline. The imprecise estimates suggest future trials will need substantially larger sample sizes or treatment modifications, such as increasing the theophylline dose, to observe larger treatment effects.

Evaluating the therapeutic effect and toxicity of theophylline in infertile men with asthenoteratozoospermia: a double-blind, randomized clinical trial study.

Theophylline as a cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitor (cAMP-PDEI) elevates cAMP levels. We aimed to evaluate the therapeutic effect and toxicity of theophylline on the sperm parameters, oxidative stress (OS), and inflammation in asthenoteratozoospermic men. Sixty asthenoteratozoospermic patients were divided into groups of placebo and theophylline (200 mg/day). After 3 months of oral treatment, sperm parameters, viability, and DNA fragmentation were analyzed by the CASA system, eosin nigrosin staining, sperm DNA fragmentation kit, respectively. The seminal plasma level of reactive oxygen species (ROS) of neat semen samples, malondialdehyde (MDA), total antioxidant capacity (TAC), tumor necrosis factor alpha (TNF-α), and interleukin-10 (IL-10) was assessed. Data were analyzed statistically using the independent samples t-test and the paired t-test and the means were considered significantly different at p < 0.05. Sperm motility, viability, and the number of sperms with normal morphology and the seminal plasma level of TAC and IL-10 and also sperm DNA fragmentation increased significantly in the theophylline group compared to the placebo. The MDA, TNF-α, and ROS levels decreased significantly in the theophylline group compared to the placebo. Theophylline improved sperm parameters, reduced OS and inflammation, but also created genotoxicity and increased sperm DNA fragmentation. Therefore, to benefit from the desired effects of theophylline and inhibit the toxicity of it in the treatment of men with asthenoteratozoospermia, it is suggested to be used simultaneously with another antioxidant to protect sperm DNA from fragmentation.

Perfusion Changes in Acute Stroke Treated with Theophylline as an Add-on to Thrombolysis : A Randomized Clinical Trial Subgroup Analysis.

PURPOSE: Theophylline has been suggested to have a neuroprotective effect in ischemic stroke; however, results from animal stroke models and clinical trials in humans are controversial. The aim of this study was to assess the effect of theophylline on the cerebral perfusion with multiparametric magnetic resonance imaging (MRI). METHODS: The relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), and relative mean transit time (rMTT) in the infarct core, penumbra, and unaffected tissue were measured using multi-parametric MRI at baseline and 3­h follow-up in patients treated with theophylline or placebo as an add-on to thrombolytic therapy. RESULTS: No significant differences in mean rCBF, rCBV, and rMTT was found in the penumbra and unaffected tissue between the theophylline group and the control group between baseline and 3­h follow-up. In the infarct core, mean rCBV increased on average by 0.05 in the theophylline group and decreased by 0.14 in the control group (p < 0.04). Mean rCBF and mean rMTT in the infarct core were similar between the two treatment groups. CONCLUSION: The results indicate that theophylline does not change the perfusion in potentially salvageable penumbral tissue but only affects the rCBV in the infarct core. In contrast to the penumbra, the infarct core is unlikely to be salvageable, which might explain why theophylline failed in clinical trials.