UNASSIGNED: Theophylline has been used for decades in human medicine for its psychostimulant, anti-inflammatory, and bronchodilator effects. Historically, in pulmonary medicine, theophylline has been used in the treatment of obstructive pulmonary diseases such as bronchial asthma (BA) or chronic obstructive pulmonary disease (COPD). This review aims to determine whether theophylline still has its place in the therapy of obstructive pulmonary diseases or whether we can even extend its use to other diagnoses such as atropine-resistant cardiac arrests, apnea of prematurity, or others. Moreover, we also aim to determine if there is a rationale for using low-dose theophylline due to its immunomodulatory and anti-inflammatory effect, or if the future of methylxanthines lies in newly synthesized derivates of theophylline such as bamifylline, or doxofylline.
UNASSIGNED: The narrative review is based on a literature search of the articles indexed in the PubMed database in 2023. We searched the database since the year 2009 using the MeSH terms \"theophylline\", \"aminophylline\", and \"methylxanthines\" and we included original articles in the English language.
UNASSIGNED: Theophylline has a number of adverse drug reactions (ADRs), the most serious of which is its effect on the cardiovascular system. It can cause severe arrhythmias or even cardiac arrest when overdosed. On the other hand, there is still a substantial amount of its applications in current clinical practice.
UNASSIGNED: There is considerable controversy associated with its use in current medicine, which can be attributed both to its narrow therapeutic range and its mentioned cardiotoxic effect. Herein, we summarize the current state-of-art of theophylline and its use in human medicine.

Caffeine and purine derivatives represent interesting chemical moieties, which show various biological activities. Caffeine is an alkaloid that belongs to the family of methylxanthine alkaloids and it is present in food, beverages, and drugs. Coffee, tea, and some other beverages are a major source of caffeine in the human diet. Caffeine can be extracted from tea or coffee using hot water with dichloromethane or chloroform and the leftover is known as decaffeinated coffee or tea. Caffeine and its derivatives were synthesized via different procedures on small and large scales. It competitively antagonizes the adenosine receptors (ARs), which are G protein-coupled receptors largely distributed in the human body, including the heart, vessels, brain, and kidneys. Recently, many reports showed the effect of caffeine derivatives in the treatment of many diseases such as Alzheimer\'s, asthma, parkinsonism, and cancer. Also, it is used as an antioxidant, anti-inflammatory, analgesic, and hypocholesterolemic agent. The present review article discusses the synthesis, reactivity, and biological and pharmacological properties of caffeine and its derivatives. The biosynthesis and biotransformation of caffeine in coffee and tea leaves and the human body were summarized in the review.

UNASSIGNED: Limited information is available regarding the direct effect of drugs prescribed to elevate intracranial pressure (ICP) in contrast to the abundance of evidence in support of medication utilized to lower ICP. Theophylline is a methylxanthine derivate used in the treatment of respiratory diseases with only a few randomized control trials or case reports describing pain improvement in low CSF pressure states or spontaneous intracranial hypotension (SIH). We present the case of a recorded increase in intracranial pressure under theophylline.
UNASSIGNED: A 23-year-old female with a complex history of hydrocephalus and syringomyelia was experiencing debilitating symptoms due to refractory intracranial hypotension. Medical management with oral theophylline was attempted for a period of three months. Intracranial pressure measurements were obtained via the telemetric pressure sensor reservoir (Miethke®, M.scio®) incorporated in the patient\'s ventriculoperitoneal shunt system.
UNASSIGNED: A significant increase in intracranial pressure was recorded at therapeutic drug levels.
UNASSIGNED: This is the first report of an increase in intracranial pressure under oral theophylline medication.

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.
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 β2-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.
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.
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.

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.

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.

Spinal anaesthesia (SA) is a common method during surgery due to easy administration, rapid effects, relaxes muscles and controls pain. But, post-dural puncture headache (PDPH) is a common problem after SA that occurs in 6%-36% of SA. We assessed the effect of four common treatment drugs sumatriptan, theophylline, pregabalin and oral caffeine on prevention of PDPH. In this systematic review, all randomized clinical trials (RCTs) during January 2015 and December 2021 were searched from PubMed, Google Scholar, Web of Science, Cochrane review and Clinical Key with a specific search strategy. The article qualities were assessed by two independent authors and were screened for relevant sources based on inclusion and exclusion criteria. Moreover, the included articles data were extracted and checked for regular basis. A total of 421 articles were identified and 193 articles were removed following a preliminary review and finally, 14 articles were included in review. Overall, we identified five RCTs on the effect of caffeine, two RCTs on the effect of sumatriptan, three RCTs on theophylline, three RCTs on pregabalin and one RCT on theophylline and sumatriptan in PDPH prevention. This review supports the effects of theophylline, pregabalin and sumatriptan in the prevention of PDPH incidence and treatment of PDPH intensity, but we cannot draw the same conclusions about caffeine due to some negative results about the caffeine effect. Nevertheless, this extracted conclusion should be considered and interpreted with caution and limited generalizations due to the small number of studies, the variety of evaluated drugs and measures, the low sample size and the bias presented.

UNASSIGNED: Electroconvulsive therapy (ECT) is a highly efficacious treatment modality used to produce seizures in patients diagnosed with major depressive disorders and psychotic episodes. In general, ECT treatment is successful in most patients; however, in some populations, ECT fails to produce adequate response. Caffeine, theophylline, and aminophylline are documented to augment seizure activity in ECT. By inhibiting adenosine, these medications can improve ECT response rate in a certain patient population. Caffeine and aminophylline have been documented to prolong seizure duration. Theophylline has been shown to improve seizure duration along with decreasing seizure threshold. All of these medications have very minimal side effect profiles. This review will discuss up-to-date evidence on the effects of xanthine derivatives in patients receiving ECT treatment.
UNASSIGNED: A literature review of PubMed and EMBASE was performed for related studies.
UNASSIGNED: Eight studies were included in our review. Premedication with caffeine, theophylline, or aminophylline was associated with increased seizure duration in patients suffering from mental disorders and were indicated to manage ECT.
UNASSIGNED: Xanthine derivatives prolong seizure duration in patients treated with ECT.

Piperine is a fascinating substance since it can be used as a biomarker in combination with other bioactive compounds or their analogues, as well as therapeutic molecules used for the healing of a variety of diseases. It displays a plentiful therapeutic potential and various health benefits when administered alone or in combination with several other drugs and/or phytochemicals. It has also been used to enhance the pharmacokinetic profile of many nutraceutical compounds like curcumin, resveratrol, quercetin, beta-carotene, barbiturates, propranolol, metformin, theophylline etc. The present review discloses the synergistic effect of piperine and its derivatives, clinical studies, and patent studies of piperine.

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.
CONCLUSIONS: 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.
BACKGROUND: • 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.
BACKGROUND: • 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.