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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.

Background: Oral bronchodilators may serve as an adjunctive therapy in patients with chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the effects of oral doxofylline and oral procaterol on lung function and clinical symptoms in COPD patients. Methods: A crossover randomized controlled trial was conducted in patients with clinically stable COPD. Participants first received either doxofylline or procaterol for 4 weeks, followed by a 1-week washout period. Assessments included the modified Medical Research Council (mMRC) dyspnea scale, COPD assessment test (CAT) scores, and 6-minute walking distance (6MWD). Pulmonary function was evaluated using spirometry with bronchodilator (BD) testing and all adverse events were recorded. Results: Twenty patients were randomly assigned to begin treatment with either doxofylline or procaterol. Their mean age was 71.7 ± 9.4 years. After four weeks of treatment, the doxofylline group showed significantly greater improvement in pulmonary function parameters (post-BD peak expiratory flow and post-BD forced expiratory flow 25–75) compared to the procaterol group. However, there were no significant differences in mMRC scores, CAT scores, or 6MWD between the two groups. More neurological adverse events were observed in the doxofylline group compared to the procaterol group (35% vs. 5%, p = 0.044). Conclusions: Doxofylline improved pulmonary function in COPD patients but did not provide superior functional performance compared to procaterol. Neurological adverse events were more frequently associated with doxofylline. Doxofylline may serve as an adjunctive therapy to enhance pulmonary function in COPD patients, but caution is advised due to its potential side effects.

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. 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. 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 (FEV ) 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. 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.

To compare the efficacy, tolerability, and safety of therapy with formoterol and oral slow-release theophylline (THEO) in patients with COPD. A randomized, parallel-group study, with double-blind arms for formoterol and placebo (PL) and an open arm for oral slow-release THEO administered in individual doses on the basis of plasma concentrations. Eighty-one centers worldwide. Eight hundred fifty-four patients with symptomatic COPD. Comparison of twice-daily inhaled formoterol dry powder (12 or 24 μg), PL, and THEO (individualized doses) over 12 months. Compared to PL, doses of formoterol and THEO both significantly improved the area under the curve for FEV1 measured over a period of 12 h following the morning dose of study medication at 3 and 12 months (p < 0.001 for all comparisons). Therapy with formoterol, 12 μg, was significantly more effective than that with THEO (p ≤ 0.026). Formoterol significantly reduced the percentage of “bad days” (ie, days with at least two individual symptom scores ≥ 2 and/or a reduction in peak expiratory flow from a baseline of > 20%; p ≤ 0.035 vs PL and THEO), and the use of salbutamol rescue medication (p ≤ 0.003 vs PL) over the whole treatment period, while the effect of THEO was similar to that of PL. Therapy with formoterol and THEO was more effective than PL at improving quality of life for > 12 months (p ≤ 0.030). Treatment-related adverse events and discontinuations were more frequent among patients receiving THEO than among those receiving formoterol. Long-term treatment with inhaled formoterol dry powder is more effective and better tolerated than treatment with therapeutically appropriate doses of oral slow-release THEO in symptomatic patients with COPD.

Bronchial asthma and chronic obstructive pulmonary disease (COPD) are the major obstructive disorders that may contribute to the severity in individual patients. The present study was designed to compare the efficacy and safety of theophylline and doxofylline in patients with bronchial asthma and COPD. A total of 60 patients, 30 each with bronchial asthma and COPD, were enrolled for the study. Each group of 30 patients received standard treatment for asthma and COPD. Each group was again subdivided into two with 15 patients each, who received theophylline or doxofylline in addition to standard therapy, for a period of 2 months. Each patient was followed up fortnightly for the assessment of efficacy parameters using a pulmonary function test (PFT), clinical symptoms and emergency drug use, and safety was assessed by recording adverse drug reactions. Both theophylline and doxofylline produced enhancements in PFT at different time intervals in both asthma and COPD patients. The maximum beneficial effects were seen at 6 weeks for asthma patients and at 8 weeks for COPD patients for both theophylline and doxofylline. The comparative study showed that doxofylline was more effective as evidenced by improvement in PFT as well as clinical symptoms, and reduced incidence of adverse effects and emergency bronchodilator use.

Patients with COPD often require multiple therapies to improve lung function and decrease symptoms and exacerbations. Salmeterol and theophylline are indicated for the treatment of COPD, but the use of these agents in combination has not been extensively studied. To compare the efficacy and safety of salmeterol plus theophylline vs either agent alone in COPD. Randomized, double-blind, double-dummy, parallel-group trial in 943 patients with COPD. After an open-label theophylline titration period (serum levels, 10 to 20μ g/mL), patients were randomly assigned to receive salmeterol (42μ g bid) plus theophylline, salmeterol (42 μg bid), or theophylline for 12 weeks. Serial pulmonary function tests were completed on day 1 and treatment week 12. Patients kept diary cards and noted their peak flow rates, symptom scores, and albuterol use, and periodically completed quality-of-life and dyspnea questionnaires. All three groups significantly improved compared with baseline. Combination treatment with salmeterol plus theophylline provided significantly (p ≤ 0.045) greater improvements in pulmonary function; significantly (p ≤ 0.048) greater decreases in symptoms, dyspnea, and albuterol use; and significantly fewer COPD exacerbations (p = 0.023 vs theophylline). In general, treatment with salmeterol provided greater improvement in lung function and satisfaction with treatment compared with theophylline. Salmeterol treatment was also associated with significantly fewer drug-related adverse events (p ≤ 0.042) than either treatment that included theophylline. The safety profile (adverse events, vital signs, and ECG findings) of the two treatments that included theophylline were similar. Patients with COPD may benefit from combination treatment with salmeterol plus theophylline, without a resulting increase in adverse events or other adverse sequelae.

Objective International guidelines recommend short- (SABA) or long-acting b-agonists for the prevention of bronchoconstriction after exercise (EIB) in patients with exercise-induced asthma (EIA). However, other drugs are still in discussion for the prevention of EIB. We investigated the efficacy of a combination of inhaled sodium cromoglycate and the β-mimetic drug reproterol versus inhaled reproterol alone and both versus inhaled placebo in subjects with exercise-induced asthma (EIA). Methods The study aimed to prove the preventive effect of a combination of 1-mg reproterol and 2-mg disodium cromoglycate (DSCG) and its single components vs. placebo, measuring the decrease of FEV1 after a standardized treadmill test in 11 patients with recorded EIA. The study medication was twice as high as those of drugs which are commercially available (e.g., Allergospasmin®, Aarane®). Results The results revealed that the combination of reproterol and DSCG was significantly effective against a decrease of FEV1 after a standardized exercise challenge test (ECT) compared to placebo. The short-acting b-agonist reproterol alone had almost the same effectiveness as the combination of reproterol and DNCG. The difference between the combination with DNCG and reproterol alone was less than 10% and insignificant ( p 0.48). DNCG alone did not show a difference in the effectiveness compared to placebo. Conclusion Prevention of EIA with the combination of reproterol and DSCG or with reproterol only is effective. An exclusive recommendation in favor of the combination cannot be given due to the low difference in the effectiveness versus reproterol alone. Due to the limited number of subjects and some probands showing protection under DSCG, it cannot be completely excluded that there is some preventive power of DSCG in individual cases.

The rationale for additional treatment of oral theophylline with inhaled therapy in patients with stable chronic obstructive pulmonary disease (COPD) is unclear. The databases including The Cochrane Library､PubMed､Embase and Web of Science were searched to collect randomized controlled trials (RCTs) involving the inhaled therapy plus additional theophylline therapy for the treatment of patients with stable COPD up to December 31, 2023. The forced expiratory volume in 1 second (FEV 1 )､forced expiratory volume in 1s% predicted (FEV 1 % pred)､forced vital capacity (FVC)､FEV 1 /FVC%､peak expiratory flow rate(PEFR)､exacerbation rate of COPD､COPD related hospital admissions､total symptom score and drug-related adverse reactions were extracted from literatures and the meta-analysis was conducted using the RevMan 5.4 software. 10 RCTs involving 2771 patients were included. The meta-analysis results showed that additional theophylline improved FEV 1 with MD 0.08 (95% CI: 0.06 to 0.09, p<0.00001)､FVC with MD 0.13 (95% CI: 0.10 to 0.15, p<0.00001), reduce the risk of exacerbation rate with OR 0.75 (95% CI: 0.60 to 0.94, p=0.01) and COPD related hospital admissions with MD -0.07 (95% CI: -0.13 to -0.01, p=0.01). However, there was no significant difference in FEV 1 % pred with MD 0.45 (95% CI: -1.41 to 2.30, p=0.64)､FEV 1 /FVC% with MD -0.24 (95% CI: -3.26 to 2.79, p=0.88) and total symptom score with MD -0.03 (95% CI: -0.14 to 0.09, p=0.65). Furthermore, additional theophylline therapy induced a high incidence of drug-related adverse reactions with OR 1.33 (95% CI: 1.12 to 1.58, p=0.001), especially in gastrointestinal adverse reactions. Oral theophylline could be a supplementary therapeutic option when inhaled therapy is insufficient regarding of improvement in pulmonary function and reducing in exacerbation risk. However, additional theophylline therapy could increase the risk of drug-related adverse reactions and should be concerned.

Doxofylline, which differs from theophylline in containing the dioxalane group at position 7, has comparable efficacy to theophylline in the treatment of respiratory diseases, but with an improved tolerability profile and a favorable risk-to-benefit ratio. Furthermore, it does not have significant drug-drug interactions as exhibited with theophylline, which make using theophylline more challenging, especially in elderly patients with co-morbidities receiving multiple classes of drug. It is now clear that doxofylline also possesses a distinct pharmacological profile from theophylline (no significant effect on any of the known phosphodiesterase isoforms, no significant adenosine receptor antagonism, no direct effect on histone deacetylases, interaction with β -adrenoceptors) and therefore, should not be considered as just a modified theophylline. Randomized clinical trials of doxofylline to investigate the use of this drug to reduce exacerbations and hospitalizations due to asthma or COPD as an alternative to expensive biologics, and certainly as an alternative to theophylline are to be encouraged.

Objective To evaluate the addition of methylxanthines to standard treatments in patients presenting with acute exacerbations of chronic obstructive pulmonary disease (COPD). Design Meta-analysis of randomised controlled trials. Data source The Cochrane airways review group's COPD register. Two reviewers independently selected articles for inclusion, assessed methodological quality, and extracted data. Selection of studies Four trials met the inclusion criteria, with 169 patients. Main outcome measures Mean change in spirometry, clinical end points, symptom scores, and adverse events. Results Mean change in forced expiratory volume at one second at two hours was similar in methylxanthine and placebo groups but transiently increased with methylxanthines at three days. Non-significant reductions in admissions to hospital and length of stay were offset by a non-significant increase in relapses at one week. Changes in symptom scores did not reach significance. Methylxanthines caused more nausea and vomiting than placebo (odds ratio 4.6, 95% confidence interval 1.7 to 12.6), and non-significant increases in tremor, palpitations, and arrhythmias were also observed. Conclusions The available data do not support the use of methylxanthines for the treatment of exacerbations of chronic obstructive pulmonary disease. Potential benefits of methylxanthines for lung function and symptoms were generally not confirmed at standard levels of significance, whereas the potentially important adverse events of nausea and vomiting were significantly increased in patients receiving methylxanthines.