Caffeine Intoxication, in Which the Theophylline Level Served as an Indicator of the Treatment Course and the Caffeine Level Could Be Measured.

A 51-year-old man presented with sudden-onset palpitations and dyspnea that had started 8 h earlier. The patient was restless and tachypneic and had persistent vomiting upon arrival. His sensorium and oxygen saturation levels rapidly declined three hours after arrival, and he was placed on a ventilator. On hospitalization day 2, he was removed from the ventilator and claimed that he had consumed a large amount of energy drinks (oral caffeine intake, approximately 1 g). The theophylline level on arrival had been elevated (9.0 µg/mL). Caffeine intoxication should be considered in patients presenting with restlessness, tachypnea, frequent vomiting, lactic acidosis, and electrolyte abnormalities.

Blood Eosinophils in Chinese COPD Participants and Response to Treatment with Combination Low-Dose Theophylline and Prednisone: A Post-Hoc Analysis of the TASCS Trial.

BACKGROUND AND OBJECTIVES: The burden of chronic obstructive pulmonary disease (COPD) disproportionately affects patients in low to middle-income countries. Although the Theophylline and Steroids in COPD Study (TASCS) showed no clinical benefit from administering low-dose theophylline and prednisone in COPD patients compared to placebo, it was hypothesized that those with elevated blood eosinophil counts would receive clinical benefit from the intervention. METHODS: This was a post-hoc analysis of the TASCS dataset - a double-blinded, placebo-controlled trial conducted in patients with moderate-severe COPD in China. Participants were allocated 1:1:1 to low-dose oral theophylline (100mg bd) and prednisone (5mg qd; PrT), theophylline (100mg bd) and prednisone-matched placebo (TP), or double-matched placebo (DP) groups and followed-up for 48 weeks. A baseline count of ≥300 eosinophils/µL blood was categorized as elevated/eosinophilic, and the primary outcome was the annualized moderate-severe exacerbation rate. RESULTS: Of 1487 participants eligible for analysis, 325 (22%) were eosinophilic. These participants were predominantly male (82%), had a mean (SD) age of 64 (±8) years and a predicted forced expiratory volume in 1s (FEV1) of 43% (±16). The annualized moderate-severe exacerbation rate was significantly higher in the PrT group compared to the pooled results of the TP and DP groups (incidence rate ratio = 1.6; ([95% CI 1.06-1.76]) p = 0.016). Changes in spirometry values and reported disease impact scores (St. George's Respiratory Questionnaire and COPD Assessment Test) at week 48 were not significantly different between groups. CONCLUSION: Combination low-dose theophylline and prednisone was associated with a significant increase in the annual moderate-severe exacerbation rate in participants with a blood eosinophil count ≥300 cells/µL compared to placebo.

Theophylline in patients with syncope without prodrome, normal heart, and normal electrocardiogram: a propensity-score matched study verified by implantable cardiac monitor.

AIMS: Syncope without prodromes in subjects with normal heart and normal electrocardiogram (ECG) is classified as non-classical neurally mediated syncope and is characterized by low adenosine plasma levels (APLs) and frequent asystolic syncope. We assessed the efficacy of theophylline, a non-selective adenosine receptor antagonist, in preventing syncopal events. METHODS AND RESULTS: Participants received an implantable cardiac monitor, underwent APL measurement, and received oral theophylline at maximum tolerated dose (starting dose 300 mg b.i.d.). They were compared with a historical cohort of untreated patients with implantable cardiac monitor who had the same inclusion criteria and were balanced with the propensity score (PS) method as regard age, sex, lifetime syncopal episodes, APL, and antihypertensive drugs. Primary endpoint was time to first syncopal recurrence at 24 months. There were 76 patients in the theophylline group and 58 in the control group. Syncope recurred in 25 (33%) patients in the theophylline group and in 27 (47%) patients in the control group, with an estimated 2-year recurrence rate of 33% and 60%, respectively, and a hazard ratio of 0.53 [95% confidence interval (CI), 0.30-0.95; P = 0.034]. Most of the benefit of theophylline is derived from reduction of syncope due to asystolic atrioventricular (AV) block (hazard ratio of 0.13; 95% CI, 0.03-0.58; P = 0.008). Thirty (39%) patients discontinued theophylline after a median of 6.4 (interquartile range 1.7-13.8) months due to side effects. CONCLUSION: Theophylline was effective in preventing recurrences in patients with syncope without prodromes, normal heart, and normal ECG. The benefit was greater in patients with syncope due to asystolic AV block. CLINICALTRIALS.GOV IDENTIFIER: NCT03803215.

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.

Dose-Response of Paraxanthine on Cognitive Function: A Double Blind, Placebo Controlled, Crossover Trial.

Paraxanthine (PXN) is a metabolite of caffeine that has recently been reported to enhance cognition at a dose of 200 mg. OBJECTIVE: To determine the acute and short-term (7-day) effects of varying doses of PXN on cognitive function and side effects. METHODS: In a double blind, placebo-controlled, crossover, and counterbalanced manner, 12 healthy male and female volunteers (22.7 ± 4 years, 165 ± 7 cm, 66.5 ± 11 kg, 24.4 ± 3 kg/m2) ingested 200 mg of a placebo (PLA), 50 mg of PXN (ENFINITY™, Ingenious Ingredients, L.P.) + 150 mg PLA, 100 mg PXN + 100 mg PLA, or 200 mg of PXN. With each treatment experiment, participants completed side effect questionnaires and donated a fasting blood sample. Participants then performed a series of tests assessing cognition, executive function, memory, and reaction time. Participants then ingested one capsule of PLA or PXN treatments. Participants then completed side effects and cognitive function tests after 1, 2, 3, 4, 5, and 6 h of treatment ingestion. Participants continued ingesting one dose of the assigned treatment daily for 6-days and returned to the lab on day 7 to donate a fasting blood sample, assess side effects, and perform cognitive function tests. Participants repeated the experiment while ingesting remaining treatments in a counterbalanced manner after at least a 7-day washout period until all treatments were assessed. RESULTS: The Sternberg Task Test (STT) 4-Letter Length Present Reaction Time tended to differ among groups (p = 0.06). Assessment of mean changes from baseline with 95% CI's revealed several significant differences among treatments in Berg-Wisconsin Card Sorting Correct Responses, Preservative Errors (PEBL), and Preservative Errors (PAR Rules). There was also evidence of significant differences among treatments in the Go/No-Go Task tests in Mean Accuracy as well as several time points of increasing complexity among STT variables. Finally, there was evidence from Psychomotor Vigilance Task Test assessment that response time improved over the series of 20 trials assessed as well as during the 6-h experiment in the PXN treatment. Acute and short-term benefits compared to PLA were seen with each dose studied but more consistent effects appeared to be at 100 mg and 200 mg doses. No significant differences were observed among treatments in clinical chemistry panels or the frequency or severity of reported side effects. Results provide evidence that acute ingestion of 100 mg and 200 mg of PXN may affect some measures of cognition, memory, reasoning, and response time as well as help sustain attention. Additionally, that acute and daily ingestion of PXN for 7 days is not associated with any clinically significant side effects. CONCLUSIONS: PXN may serve as an effective nootropic agent at doses as low as 50 mg.

An assessment of mutagenicity, genotoxicity, acute-, subacute and subchronic oral toxicity of paraxanthine (1,7-dimethylxanthine).

Paraxanthine or 1,7-dimethylxanthine is a natural dietary component and the main metabolite of caffeine in humans. A battery of toxicological studies was conducted in accordance with international guidelines to investigate mutagenicity, genotoxicity and acute and repeated-dose oral toxicity in rats of synthetic paraxanthine (ENFINITY™, Ingenious Ingredients, L.P., >99% purity). There was no evidence of mutagenicity in a bacterial reverse mutation as well as in an in vitro mammalian chromosomal aberration test. There was no evidence of genotoxicity in an in vivo mammalian erythrocyte micronucleus test as well as in an in vitro mammalian cell gene mutation test. An acute oral toxicity test resulted in a LD50 value of 1601 mg/kg bw/d. Paraxanthine did not cause mortality or toxic effects in a subacute 28-day repeated-dose oral toxicity study at daily doses of 75, 150, or 300 mg/kg bw/d (each group n = 10 per sex), administered by gavage. Paraxanthine also did not cause mortality or toxic effects in a subchronic 90-day repeated-dose oral toxicity study at daily doses of 75, 150, or 300 mg/kg bw/d (each group n = 10 per sex), administered by gavage. The no observed adverse effect level (NOAEL) determined from the 90-day study was greater than or equal to 300 mg/kg bw/d, the highest dose tested, for both male and female Wistar rats.

Investigating the Relations Between Caffeine-Derived Metabolites and Plasma Lipids in 2 Population-Based Studies.

OBJECTIVE: To investigate the relations between caffeine-derived metabolites (methylxanthines) and plasma lipids by use of population-based data from 2 European countries. METHODS: Families were randomly selected from the general population of northern Belgium (FLEMENGHO), from August 12, 1985, until November 22, 1990, and 3 Swiss cities (SKIPOGH), from November 25, 2009, through April 4, 2013. We measured plasma concentrations (FLEMENGHO, SKIPOGH) and 24-hour urinary excretions (SKIPOGH) of 4 methylxanthines-caffeine, paraxanthine, theobromine, and theophylline-using ultra-high-performance liquid chromatography-tandem mass spectrometry. We used enzymatic methods to estimate total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels and the Friedewald equation for low-density lipoprotein cholesterol levels in plasma. We applied sex-specific mixed models to investigate associations between methylxanthines and plasma lipids, adjusting for major confounders. RESULTS: In both FLEMENGHO (N=1987; 1055 [53%] female participants) and SKIPOGH (N=990; 523 [53%] female participants), total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels increased across quartiles of plasma caffeine, paraxanthine, and theophylline (total cholesterol levels by caffeine quartiles in FLEMENGHO, male participants: 5.01±0.06 mmol/L, 5.05±0.06 mmol/L, 5.27±0.06 mmol/L, 5.62±0.06 mmol/L; female participants: 5.24±0.06 mmol/L, 5.15±0.05 mmol/L, 5.25±0.05 mmol/L, 5.42±0.05 mmol/L). Similar results were observed using urinary methylxanthines in SKIPOGH (total cholesterol levels by caffeine quartiles, male participants: 4.54±0.08 mmol/L, 4.94±0.08 mmol/L, 4.87±0.08 mmol/L, 5.27±0.09 mmol/L; female participants: 5.12±0.07 mmol/L, 5.21±0.07 mmol/L, 5.28±0.05 mmol/L, 5.28±0.07 mmol/L). Furthermore, urinary caffeine and theophylline were positively associated with high-density lipoprotein cholesterol in SKIPOGH male participants. CONCLUSION: Plasma and urinary caffeine, paraxanthine, and theophylline were positively associated with plasma lipids, whereas the associations involving theobromine were less clear. We postulate that the positive association between caffeine intake and plasma lipids may be related to the sympathomimetic function of methylxanthines, mitigating the overall health-beneficial effect of caffeine intake.

Reflux esophagitis in patients with chronic obstructive pulmonary disease.

ABSTRACT: The relationship between chronic obstructive pulmonary disease (COPD) and reflux esophagitis (RE) was controversial. We investigated the factors influencing RE development in patients with COPD and evaluated the association between RE and AECOPD.Patients with COPD who underwent esophagogastroduodenoscopy from January 2003 to December 2013 in St. Paul's Hospital, the Catholic University of Korea (Seoul, Korea) were enrolled retrospectively. The grade of RE was based on the Los Angeles classification and minimal change esophagitis. Body mass index, smoking history, medical history, AECOPD, pulmonary function test data, endoscopic findings, and comorbidities were reviewed.Of a total of 218 patients with COPD, 111 (50.9%) were diagnosed with RE. None of age, sex, smoking history, or the severity of airflow limitation was associated with RE. AECOPD was not related to either the presence or severity of RE. There was no significant correlation between RE grade by Los Angeles classification and severity of airflow limitation (P = .625). Those who had RE used theophylline (P = .003) and long-acting muscarinic antagonists (P = .026) significantly more often than did controls. The use of theophylline (OR 2.05; 95% CI, 1.16-3.65, P = .014) was associated with an increased incidence of RE.The use of theophylline might increase the risk of RE in COPD patients. RE may not be associated with airflow limitation or AECOPD.

Multidose pharmacokinetics and safety of a modified, compounded theophylline product in dogs.

Theophylline is used in canine medicine for the management of chronic bronchitis and bradyarrhythmias, yet no species-validated commercial products are available. This study reports the single-dose and multidose pharmacokinetics and safety of a modified, compounded theophylline (MCT) product readily available from a well-established, USP-compliant compounding pharmacy, which may be a suitable and reliable source for theophylline for dogs. Eleven dogs underwent serial plasma theophylline measurement following 10 mg/kg MCT PO. After a 7 days washout, dogs received 10 mg/kg MCT PO q12h and serial plasma theophylline quantification was repeated after the ninth dose. Dogs were monitored for potential adverse effects. For the nine dogs that completed the study, plasma theophylline concentrations were between 5 and 30 µg/ml for 91 +/- 15% of the dosing interval. There was no significant difference in half-life between single-dose and multidose administration. The most common adverse effects reported were mild and included agitation, excitement, and increased activity. The results of this study support the use of 10 mg/kg MCT administered twice daily as a starting dosage in dogs. This regimen appears safe, achieves appropriate plasma drug concentrations in most dogs, and does not cause significant changes in pharmacokinetic properties at steady state. Because compounded drugs do not undergo consistent testing for identity, quality, strength, purity, and stability, results of research described in reports using compounded products may not be reproducible.

[Nonconvulsive Status Epilepticus Associated with Theophylline: A Case Report].

An 87-year-old woman was admitted to our hospital because of speech disturbance and right facio-pharyngo-glosso-masticatory diplegia. She had bronchial asthma, was previously diagnosed with cerebral infarction, had experienced two events of convulsive status epilepticus, and was undergoing treatment with theophylline, levetiracetam, and clopidogrel. Head diffusion-weighted magnetic resonance imaging revealed a high-signal area in the left crus posterior capsula interna. For this, we administered cilostazol along with her regular medicines. On day 14, she had tonic-clonic convulsions, extending from the right upper and lower limbs to the whole body. Subsequently, cilostazol was discontinued, and the dose of levetiracetam was increased. However, she developed severe tonic-clonic seizures with right sensory aphasia and right hemiplegia, for which an increased dose of lacosamide was added. When theophylline was discontinued 5 days after the onset of convulsions, the blood concentration of theophylline was 9.7µg/mL. After theophylline was discontinued, tonic-clonic convulsions improved. The disturbance of consciousness and right hemiparesis were improved after one week, while the disturbance of sensory aphasia was improved after one month. We suspect that cerebral infarction may have aggravated the central nervous system damage caused by theophylline, thereby resulting in aminophylline-related non-convulsive status epilepticus. (Received 20 July 2020; Accepted 27 October 2020; Published 1 March 2021).

Effectiveness of low-dose theophylline for the management of biomass-associated COPD (LODOT-BCOPD): study protocol for a randomized controlled trial.

BACKGROUND: COPD is a leading cause of death globally, with the majority of morbidity and mortality occurring in low- and middle-income country (LMIC) settings. While tobacco-smoke exposure is the most important risk factor for COPD in high-income settings, household air pollution from biomass smoke combustion is a leading risk factor for COPD in LMICs. Despite the high burden of biomass smoke-related COPD, few studies have evaluated the efficacy of pharmacotherapy in this context. Currently recommended inhaler-based therapy for COPD is neither available nor affordable in most resource-limited settings. Low-dose theophylline is an oral, once-a-day therapy, long used in high-income countries (HICs), which has been proposed for the management of COPD in LMICs in the absence of inhaled steroids and/or bronchodilators. The Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD) trial investigates the clinical efficacy and cost-effectiveness of low-dose theophylline for the management of biomass-related COPD in a low-income setting. METHODS: LODOT-BCOPD is a randomized, double-blind, placebo-controlled trial to test the efficacy of low-dose theophylline in improving respiratory symptoms in 110 participants with moderate to severe COPD in Central Uganda. The inclusion criteria are as follows: (1) age 40 to 80 years, (2) full-time resident of the study area, (3) daily biomass exposure, (4) post-bronchodilator FEV1/FVC below the 5th percentile of the Global Lung Initiative mixed ethnic reference population, and (5) GOLD Grade B-D COPD. Participants will be randomly assigned to receive once daily low-dose theophylline (200 mg ER, Unicontin-E) or placebo for 52 weeks. All participants will receive education about self-management of COPD and rescue salbutamol inhalers. We will measure health status using the St. George's Respiratory Questionnaire (SGRQ) and quality of life using the EuroQol-5D (EQ-5D) at baseline and every 6 months. In addition, we will assess household air pollution levels, serum inflammatory biomarkers (fibrinogen, hs-CRP), and theophylline levels at baseline, 1 month, and 6 months. The primary outcome is change in SGRQ score at 12 months. Lastly, we will assess the cost-effectiveness of the intervention by calculating quality-adjusted life years (QALYs) from the EQ-5D. TRIAL REGISTRATION: ClinicalTrials.gov  NCT03984188 . Registered on June 12, 2019 TRIAL ACRONYM: Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD).

Positive chronotropic effects of theophylline and cilostazol in patients with symptomatic sick sinus syndrome who have declined permanent pacing.

Pacemakers are more commonly recommended than theophylline for sick sinus syndrome (SSS) treatment. The positive effects of cilostazol on bradyarrhythmias also have been reported. However, no comparison of cilostazol and theophylline has been previously reported found. We retrospectively enrolled SSS patients, who refused a pacemaker implantation. Theophylline or cilostazol was administered, and the heart rate (HR) was evaluated in 4-8 weeks using a digital sphygmomanometer and the electrocardiogram (ECG). A 200-400 mg of theophylline or 100-200 mg of cilostazol were administered per day in 50 and 30 patients, respectively. The baseline HR was 54.8 ± 13.5 beats per minute (bpm) on using sphygmomanometry and 51.9 ± 11.8 bpm using the ECG. In the theophylline group, the HR increased by 12.0 ± 16.3 bpm by sphygmomanometry (P < 0.001) and 8.4 ± 12.0 bpm by the ECG (P < 0.001). In the cilostazol group, the HR increased by 16.8 ± 13.9 bpm by sphygmomanometry (P < 0.001) and 12.4 ± 13.4 bpm using the ECG (P < 0.001). In 15 of the 50 theophylline patients, the medication was switched to cilostazol. The HR increased from 61.4 ± 13.8 bpm to 64.0 ± 12.6 bpm (P = 0.338). Symptoms such as dyspnea, chest discomfort, dizziness, and syncope significantly improved after the administration of the medications. There were no significant differences in the improvement in the symptoms except for dizziness between the two agents. Cilostazol was as effective as theophylline for increasing the HR in SSS patients.

Safety of regadenoson with theophylline reversal during dynamic computed tomography perfusion and magnetic resonance imaging in patients with coronary artery disease.

BACKGROUND: The use of regadenoson in dynamic computed tomography perfusion (CTP) and magnetic resonance myocardial perfusion imaging (MR MPI) is off­label. AIMS: The study aimed to assess the safety of regadenoson with theophylline reversal during CTP and MR MPI in patients with coronary artery disease (CAD). METHODS: In this prospective study, patients with 1 or more intermediate coronary artery stenoses on computed tomography angiography underwent CTP and MR MPI with 0.4 mg of regadenoson. After examinations, 200 mg of theophylline was given intravenously in 100 ml of saline. Changes in blood pressure (BP) and heart rate (HR) were repeatedly assessed. All side effects and adverse events were recorded. RESULTS: Out of 106 examinations in 53 patients (25 females, 63.5 [8.5] years), all were diagnostic. There were no deaths, myocardial infarctions, severe arrhythmias, high­grade atrioventricular blocks, or bronchospasms. The most common symptoms were palpitations (17%), hot flushing (8%), chest discomfort (4%), and mild dyspnea (3%). There were no differences between baseline and peak BP. There was an increase in median (interquartile range) peak HR after regadenoson as compared with baseline (MR MPI, 63 [59-75] bpm vs 93 [86-102] bpm; P <0.001; and CTP, 65 [60-70] bpm vs 95 [86-107] bpm; P <0.001). The hemodynamic response to regadenoson and its side effects were completely reversible by theophylline. CONCLUSIONS: Regadenoson may be a safe vasodilator for CTP and MR MPI in patients with CAD. The administration of theophylline after perfusion is safe and reverses side effects of regadenoson.

The effect of doxofylline in asthma and COPD.

Theophylline is still one of the most widely prescribed drugs for the treatment of asthma and COPD in developing countries because the majority of asthma and COPD medicines are largely unavailable and also because it is a cheap option. In any case, its anti-inflammatory effects and capacity to reverse corticosteroid resistance deserve consideration, but it can induce numerous side effects and drug-drug interactions and frequently requires measurement of drug levels in plasma. In order to overcome the problems posed by theophylline, other xanthines have been developed. Doxofylline is a newer generation xanthine with both bronchodilating and anti-inflammatory activities and for this reason it has been called "novofylline". It differs substantially from theophylline at the pharmacological level. Clinical studies have shown substantial differences between doxofylline and theophylline. In particular, efficacy/safety profile of doxofylline is better than that of theophylline.

A long-term clinical trial on the efficacy and safety profile of doxofylline in Asthma: The LESDA study.

Doxofylline, an oral methylxanthine with bronchodilator and anti-inflammatory activities, offers a promising alternative to theophylline due to its superior efficacy/safety profile. No long-term studies on the efficacy and safety of doxofylline are currently available in asthma. The aim of the Long-term clinical trial on the Efficacy and Safety profile of Doxofylline in Asthma (LESDA) study was to investigate the safety and efficacy profile of doxofylline administered for one year in asthmatic patients. LESDA was a multicenter, open-label, Phase III, clinical trial in which adult asthmatic patients received the same treatment (oral doxofylline 400 mg t.i.d.) for one year. Efficacy was assessed through periodic pulmonary function tests and by having the subjects keep monthly records of asthma events rates and use of salbutamol as rescue medication. The rate of adverse events (AEs) was recorded during the study. Three-hundred nine patients were screened and allocated in the study. Doxofylline significantly improved the change from baseline in forced expiratory volume in 1 s (FEV1) (+16.90 ± 1.81%, P < 0.001 vs. baseline). Doxofylline also significantly improved the rate of asthma events (events/day: -0.57 ± 0.18, P < 0.05 vs. baseline) and the use of salbutamol as rescue medication (puffs/day: -1.48 ± 0.25, P < 0.01 vs. baseline). The most common AEs were nausea (14.56%), headache (14.24%), insomnia (10.68%), and dyspepsia (10.03%). There were neither serious AEs nor deaths during or shortly after the study. Concluding, doxofylline is effective and well tolerated when administered chronically in asthmatic patients.

Use of dimethylxanthine theophylline (SpermMobil®) does not affect clinical, obstetric or perinatal outcomes.

PURPOSE: To evaluate whether the use of a commercially available dimethylxanthine theophylline compound (SpermMobil®) for artificial sperm activation would negatively affect clinical, obstetric and perinatal outcomes. METHODS: Artificial sperm activation (ASA) was used when sperm motility after preparation was low or absent in our clinical standard procedure practice. ICSI cycles using either testicular or ejaculated sperm with concentration smaller than 5 million/ml from August 2012 to January 2018 were retrospectively analyzed (n = 815) and divided into two groups, a control group where no ASA was needed and the SpermMobil® group with ASA. RESULTS: The fertilization rate was significantly higher in the control group, but pregnancy and implantation rates did not differ significantly. Number of embryos transferred, good quality embryos for ET and number of frozen blastocysts were similar in both groups. Clinical pregnancy loss was significantly reduced in the SpermMobil® group, which was reflected in slightly better live birth rates than in the control group. Furthermore, there were no significant differences regarding gestational age, weight, height and z score for singletons or multiples in the SpermMobil® (n = 27 and n = 10) or control (n = 144 and n = 67) groups. There were no reports of malformation, perinatal mortality or intensive therapy in the SpermMobil® group, whereas in the control group, 12 babies needed intensive care, besides one intrauterine death. CONCLUSION: The use of SpermMobil® in samples with mostly immotile sperm not only facilitates the embryologists work but also optimizes the treatment outcomes for those patients with a bad prognosis. This is the first report of obstetric and perinatal outcomes after applying a theophylline derivative in human clinical use.

Prevalence and recognition of highly significant medication-smoking cessation interactions in a smoke-free hospital.

BACKGROUND: Some medications are more rapidly metabolized by smokers; upon smoking cessation, medication metabolism may be significantly reduced, resulting in medication-related adverse events. Clozapine, olanzapine and theophylline have been deemed to have potentially highly significant interactions with smoking cessation, which could lead to seizures, extrapyramidal effects and tachycardia, respectively. This study examined the period prevalence and characteristics of patients at risk of highly significant medication-smoking cessation interactions when admitted to a smoke-free hospital. METHODS: A retrospective cross-sectional study was undertaken in an Australian tertiary-referral hospital with a well-established electronic prescribing system. Smokers prescribed clozapine, olanzapine or theophylline prior to and during a hospital admission in 2015 were included. Length of hospital stay, daily doses, and recognition of the potential interaction by treating clinicians were determined from medical records. RESULTS: The period prevalence of patients at risk of a potentially highly significant medication-smoking cessation interaction was 23/48 (48%), 66/256 (26%) and 1/16 (6%) amongst smokers prescribed clozapine, olanzapine or theophylline, respectively. These interactions were poorly recognized by healthcare professionals during the admission. CONCLUSIONS: Up to one in two patients receiving medications that have potentially highly significant interactions with smoking cessation may be experiencing clinically significant potential interactions. Such interactions, however, were commonly overlooked by hospital staff. Interventions to improve awareness of this issue are warranted.

Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD: A Randomized Clinical Trial.

Importance: Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD. Objective: To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD. Design, Setting, and Participants: The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites. Interventions: Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787). Main Outcomes and Measures: The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period. Results: Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%). Conclusions and Relevance: Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations. Trial Registration: isrctn.org Identifier: ISRCTN27066620.

Impact of doxofylline compared to theophylline in asthma: A pooled analysis of functional and clinical outcomes from two multicentre, double-blind, randomized studies (DOROTHEO 1 and DOROTHEO 2).

This pooled analysis of double-blind, randomized, placebo-controlled trials aimed to investigate the impact of DOxofylline compaRed tO THEOphylline (DOROTHEO 1 and DOROTHEO 2 studies) on functional and clinical outcomes in asthma. Asthmatic patients ≥16 years of age with forced expiratory volume in 1 s (FEV1) ≥50% and <80% and with ≥15% post-bronchodilator increase in FEV1 were randomized in a 1:1:1:1 ratio in DOROTHEO 1 to receive doxofylline 200 mg, doxofylline 400 mg, theophylline 250 mg, or placebo; in DOROTHEO 2 patients were randomized in a 1:1:1 ratio to receive doxofylline 400 mg, theophylline 250 mg, or placebo. All double-blind treatments were taken orally with immediate release formulations and three times daily. Data evaluating the effect of doxofylline 400 mg, theophylline 250 mg and placebo on FEV1, asthma events rate, use of salbutamol as rescue medication and adverse events (AEs) were pooled from both studies. The pooled-analysis of 483 patients demonstrated that both doxofylline 400 mg and theophylline 250 mg significantly increased FEV1, reduced the rate of asthma events and use of salbutamol to relieve asthma symptoms compared to placebo (p < 0.01). No significant differences were detected between doxofylline 400 mg and theophylline 250 mg. Doxofylline 400 mg did not significantly (p > 0.05) increase the risk of AEs compared to placebo, conversely in patients treated with theophylline 250 mg the risk of AEs was significantly (p < 0.05) greater than in those that received placebo. We conclude that doxofylline seems to offer a promising alternative to theophylline with a superior efficacy/safety profile in the management of patients with asthma.