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.

Mechanistic actions of oxygen and methylxanthines on respiratory neural control and for the treatment of neonatal apnea.

Apnea remains one of the most concerning and prevalent respiratory disorders spanning all ages from infants (particularly those born preterm) to adults. Although the pathophysiological consequences of apnea are fairly well described, the neural mechanisms underlying the etiology of the different types of apnea (central, obstructive, and mixed) still remain incompletely understood. From a developmental perspective, however, research into the respiratory neural control system of immature animals has shed light on both central and peripheral neural pathways underlying apnea of prematurity (AOP), a highly prevalent respiratory disorder of preterm infants. Animal studies have also been fundamental in furthering our understanding of how clinical interventions (e.g. pharmacological and mechanical) exert their beneficial effects in the clinical treatment of apnea. Although current clinical interventions such as supplemental O2 and positive pressure respiratory support are critically important for the infant in respiratory distress, they are not fully effective and can also come with unfortunate, unintended (and long-term) side-effects. In this review, we have chosen AOP as one of the most common clinical scenarios involving apnea to highlight the mechanistic basis behind how some of the interventions could be both beneficial and also deleterious to the respiratory neural control system. We have included a section on infants with critical congenital heart diseases (CCHD), in whom apnea can be a clinical concern due to treatment with prostaglandin, and who may benefit from some of the treatments used for AOP.

Prescription Status and Clinical Outcomes of Methylxanthines and Leukotriene Receptor Antagonists in Mild-to-Moderate Chronic Obstructive Pulmonary Disease.

Background: Methylxanthines and leukotriene receptor antagonists (LTRA) are not a first-line medical treatment for chronic obstructive pulmonary disease (COPD) but are frequently prescribed despite limited evidence. We aimed to elucidate the real prescribing status and clinical impacts of these agents in early COPD patients. Methods: Patients with mild-to-moderate COPD (FEV1>50%) were selected from the Korean National Health and Nutrition Examination Survey data between 2007 and 2012. Besides analyzing the prescription status of methylxanthines and LTRA and the contributing factors to the prescription, we evaluated the clinical impacts of these drugs on the exacerbation, hospitalization, and medical costs. Results: Of 2269 patients with mild-to-moderate COPD, 378 patients (16.7%) were under medical treatments, and the users of methylxanthines and/or LTRA were 279 patients (12.3%); however, only 139 patients (6.1%) were inhaler users. The contributing factors for the prescription of methylxanthines were a comorbidity of asthma or allergic disease, poor lung function, low quality of life, prescribing doctor from the specialty of internal medicine, and an institution type of private hospital. The prescription of LTRA was associated with the comorbidity of allergic disease. The methylxanthine and/or LTRA users had more hospital utilization but did not have significant differences in acute exacerbations and medical cost for hospital utilization, compared with the non-users. Conclusion: Methylxanthines and LTRA were used in a significant proportion of patients with mild-to-moderate COPD in real fields without favorable impacts on the exacerbations, hospitalizations, or medical costs. The use of more effective inhaled medications should be encouraged.

Risperidone Combination Therapy With Propentofylline for Treatment of Irritability in Autism Spectrum Disorders: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

OBJECTIVES: Propentofylline is a xanthine phosphodiesterase inhibitor and adenosine reuptake blocker with neuroprotective effects linked to anti-inflammatory and antiexcitatory properties. This is a double-blind, placebo-controlled trial investigating the potential beneficial effects of propentofylline, as an adjunctive treatment with risperidone, on the severity and behavioral abnormalities of autism spectrum disorder (ASD). METHODS: A total of 48 children with ASD were randomly allocated into 2 groups of risperidone (initiating at 0.5 mg/d) plus propentofylline (initiating at 300 mg/d) and risperidone plus placebo. The Aberrant Behavior Checklist-Community (ABC-C) and Childhood Autism Rating Scale (CARS) were used for the evaluation of ASD severity and behavioral disruptions at baseline, week 4, and week 10. Primary outcome measure of the study was ABC-C irritability subscale score, whereas CARS score along with other 4 subscales of ABC-C (lethargy/social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech subscales) were considered as secondary outcome measures. RESULTS: Results from the general linear model repeated measures analysis demonstrated significant time-treatment interaction on irritability subscale (F1.55 = 3.45; P = 0.048) and CARS (F1.41 = 4.08; P = 0.034) scores. Compared with the placebo group, children receiving propentofylline showed greater improvements in the CARS score (P = 0.037) from baseline to the study endpoint. Our results found no significant time-treatment effect on other subscales of ABC-C. Two trial groups were comparable based on the frequency of adverse effects. CONCLUSIONS: Our findings demonstrated that adjunctive treatment with propentofylline is effective in alleviating disease severity and improving irritability in ASD patients. However, larger studies with longer durations are required to confirm these results.

A Randomized, Placebo-Controlled Trial to Assess the Effects of 8 Weeks of Administration of GSK256073, a Selective GPR109A Agonist, on High-Density Lipoprotein Cholesterol in Subjects With Dyslipidemia.

GPR109A (HM74A), a G-protein-coupled receptor, is hypothesized to mediate lipid and lipoprotein changes and dermal flushing associated with niacin administration. GSK256073 (8-chloro-3-pentyl-1H-purine-2,6[3H,7H]-dione) is a selective GPR109A agonist shown to suppress fatty acid levels and produce mild flushing in short-term clinical studies. This study evaluated the effects of GSK256073 on lipids in subjects with low high-density lipoprotein cholesterol (HDLc). Subjects (n = 80) were randomized (1:1:1:1) to receive GSK256073 5, 50, or 150 mg/day or matching placebo for 8 weeks. The primary end point was determining the GSK256073 exposure-response relationship for change from baseline in HDLc. No significant exposure response was observed between GSK256073 and HDLc levels. GSK256073 did not significantly alter HDLc levels versus placebo, but rather revealed a trend at the 150-mg dose for a nonsignificant decrease in HDLc (-6.31%; P = .12) and an increase in triglycerides (median, 24.4%; 95% confidence interval, 7.3%-41.6%). Flushing was reported in 21%, 25%, and 60% of subjects (5, 50, and 150 mg, respectively) versus 24% for placebo. Results indicated that selective activation of the GPR109A receptor with GSK256073 did not produce niacin-like lipid effects. These findings add to the increasing evidence that niacin-mediated lipoprotein changes occur predominantly via GPR109A-independent pathways.

Chocolate and chocolate constituents influence bone health and osteoporosis risk.

Bone loss resulting in increased risk for osteoporosis is a major health issue worldwide. Chocolate is a rich source of antioxidant and antiinflammatory flavonoids and dietary minerals with the potential to benefit bone health. However, other chocolate constituents such as cocoa butter, sugar, and methylxanthines may be detrimental to bone. Human studies investigating the role of chocolate consumption on serum bone markers and bone mineral density (BMD) have been inconsistent. A contributing factor is likely the different composition and thereby the nutrient and bioactive content among chocolate types. White and milk chocolate are high in sugar and low in flavonoids and most minerals. Dark chocolate (45-85% cocoa solids) is high in flavonoids, most minerals, and low in sugar with ≥70% cocoa solids resulting in higher fat and methylxanthine content. The aim of this review was to examine the relationship between chocolate consumption and its constiuents, including flavonoid content, on bone health and osteoporosis risk. Studies showed postmenopausal women had no bone effects at moderate chocolate intakes, whereas adolescents consuming chocolate had greater longitudinal bone growth. Based on flavonoid and mineral content, unsweetened cocoa powder appeared to be the best option followed by dark chocolate with higher cocoa content in terms of supporting and preserving bone health. Determining dietary recommendations for chocolate consumption relative to bone health is important because of the growing popularity of chocolate, particularly dark chocolate, and an expected increase in consumption owing to suggestions of health benefits against various degenerative diseases.

Efficacy and safety profile of xanthines in COPD: a network meta-analysis.

Theophylline can still have a role in the management of stable chronic obstructive pulmonary disease (COPD), but its use remains controversial, mainly due to its narrow therapeutic window. Doxofylline, another xanthine, is an effective bronchodilator and displays a better safety profile than theophylline. Therefore, we performed a quantitative synthesis to compare the efficacy and safety profile of different xanthines in COPD.The primary end-point of this meta-analysis was the impact of xanthines on lung function. In addition, we assessed the risk of adverse events by normalising data on safety as a function of person-weeks. Data obtained from 998 COPD patients were selected from 14 studies and meta-analysed using a network approach.The combined surface under the cumulative ranking curve (SUCRA) analysis of efficacy (change from baseline in forced expiratory volume in 1 s) and safety (risk of adverse events) showed that doxofylline was superior to aminophylline (comparable efficacy and significantly better safety), bamiphylline (significantly better efficacy and comparable safety), and theophylline (comparable efficacy and significantly better safety).Considering the overall efficacy/safety profile of the investigated agents, the results of this quantitative synthesis suggest that doxofylline seems to be the best xanthine for the treatment of COPD.

Blood potassium and urine aldosterone after doxapram therapy for preterm infants.

OBJECTIVE: We often encounter infants who developed hypokalaemia following low-dose doxapram for apnea of prematurity (AOP). AIMS: To determine changes in blood potassium (K+) levels after doxapram administration. STUDY DESIGN: We studied infants born before 30 weeks gestation. Doxapram (0.1-0.3 mg/kg/h) in addition to methylxanthines was used to treat AOP refractory to methylxanthines. RESULTS: Twenty-five infants received doxapram were studied. Fifty-two percent developed hypokalemia (<3.0 mEq/L) during doxapram administration. Time after starting doxapram to nadir blood K+ (<3.0 mEq/L) level was 11 days. Blood K+ levels normalized after 5 days of stopping doxapram administration. Data at 10 days before and after and at the time of doxapram administration were, respectively: lowest blood K+ level: 3.9, 3.0, and 3.6 mEq/L; urine aldosterone: 90, 206, and 146 pg/µg creatinine. Blood pH, blood pressure and urine volume were similar. CONCLUSIONS: Doxapram-induced hypokalemia may be due to an inappropriate increase in aldosterone levels.

Medications that relax the lower oesophageal sphincter and risk of oesophageal cancer: An analysis of two independent population-based databases.

Excessive lower oesophageal sphincter relaxation increases gastro-oesophageal acid reflux, an oesophageal adenocarcinoma risk factor. Medications that relax this sphincter (benzodiazepines, calcium channel blockers, nitrates, ß2 agonists and xanthines) could promote cancer. These medications were investigated in two independent datasets. In the Scottish Primary Care Clinical Informatics Unit (PCCIU) database, a nested case-control study of oesophageal cancer was performed using GP prescription records. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs) for medication use and oesophageal cancer. In UK Biobank, a cohort study was conducted using self-reported medication use. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs for medication use and oesophageal cancer, and by tumour subtype. Overall, 1,979 oesophageal cancer patients were matched to 9,543 controls in PCCIU, and 355 of 475,768 participants developed oesophageal cancer in UK Biobank. None of the medications investigated were significantly associated with oesophageal cancer risk apart from ß2 agonists, which were associated with increased oesophageal cancer risk in PCCIU (adjusted OR 1.38, 95% CI 1.12, 1.70) but not in UK Biobank (adjusted HR 1.21, 95% CI 0.70, 2.08). Medications that relax the lower oesophageal sphincter were not associated with oesophageal cancer, apart from ß2 agonists. This increased cancer risk in ß2 agonist users merits further investigation.

Xanthines and Phosphodiesterase Inhibitors.

Theophylline is an orally acting xanthine that has been used since 1937 for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, in most treatment guidelines, xanthines have now been consigned to third-line therapy because of their narrow therapeutic window and propensity for drug-drug interactions. However, lower than conventional doses of theophylline considered to be bronchodilator are now known to have anti-inflammatory actions of relevance to the treatment of respiratory disease. The molecular mechanism(s) of action of theophylline are not well understood, but several potential targets have been suggested including non-selective inhibition of phosphodiesterases (PDE), inhibition of phosphoinositide 3-kinase, adenosine receptor antagonism and increased activity of certain histone deacetylases. Although theophylline has a narrow therapeutic window, other xanthines are in clinical use that are claimed to have a better tolerability such as doxofylline and bamifylline. Nonetheless, xanthines still play an important role in the treatment of asthma and COPD as they can show clinical benefit in patients who are refractory to glucocorticosteroid therapy, and withdrawal of xanthines from patients causes worsening of disease, even in patients taking concomitant glucocorticosteroids.More recently the orally active selective PDE4 inhibitor, roflumilast, has been introduced into clinical practice for the treatment of severe COPD on top of gold standard treatment. This drug has been shown to improve lung function in patients with severe COPD and to reduce exacerbations, but is dose limited by a range side effect, particularly gastrointestinal side effects.

Hypochloremia, Diuretic Resistance, and Outcome in Patients With Acute Heart Failure.

BACKGROUND: Chloride plays a role in renal salt sensing, neurohormonal activation, and regulation of diuretic targets, and hypochloremia predicts mortality in acute heart failure (AHF). AHF therapies, such as diuretics, alter chloride homeostasis. We studied the association between (changes in) chloride levels and diuretic responsiveness, decongestion, and mortality in patients with AHF. METHODS AND RESULTS: Patients hospitalized for AHF in the PROTECT trial (n=2033) with serum chloride levels within 24 hours of admission and 14 days later were studied (n=1960). Hypochloremia was defined as serum chloride <96 mEq/L. Mean baseline chloride was 100.8±5.0 mEq/L. Low baseline chloride was associated with high bicarbonate, poor diuretic response, less hemoconcentration, and worsening heart failure (all P<0.01). Newly developed hypochloremia at day 14 was common and associated with a decline in renal function and an increase in blood urea nitrogen (P<0.01). In multivariable analyses, chloride measured at day 14, but not baseline chloride, was strongly and independently associated with mortality through 180 days (hazard ratio per unit decrease: 1.07 [1.03-1.10]; P<0.001). In comparison, sodium was not significantly associated with mortality after multivariable adjustment at any time point. Hypochloremia at baseline that resolved was not associated with mortality (P=0.55), but new or persistent hypochloremia at day 14 was associated with increased mortality (hazard ratio: 3.11 [2.17-4.46]; P<0.001). CONCLUSIONS: Low serum chloride at AHF hospital admission was strongly associated with impaired decongestion. New or persistent hypochloremia 14 days later was independently associated with reduced survival, whereas hypochloremia that resolved by day 14 was not. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00354458.

Combining Diuretic Response and Hemoconcentration to Predict Rehospitalization After Admission for Acute Heart Failure.

BACKGROUND: Both diuretic response and hemoconcentration are indicators of decongestion and have individually been found to predict rehospitalization after admission for acute heart failure (HF). This study examines the value of combining diuretic response and hemoconcentration to better predict patients at low risk for rehospitalization after admission for acute HF. METHODS AND RESULTS: Diuretic response (defined as weight change per 40 mg of furosemide on day 4 after admission) and hemoconcentration (change in hemoglobin at discharge or day 7) were tested both individually and combined to predict the risk of HF and cardiovascular rehospitalization 60 days after hospitalization for acute HF. Analyses were performed in 1180 patients enrolled in the Placebo-Controlled Randomized Study of the Selective Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) trial and validated in 1776 patients enrolled in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial. Poor diuretic response was associated with low systolic blood pressure, high blood urea nitrogen, and history of coronary revascularization in both data sets (all P<0.05). Hemoconcentration was mainly associated with better renal function (P<0.05). Patients who displayed both favorable diuretic response and hemoconcentration had a markedly lower risk of rehospitalization for HF in PROTECT (multivariable HR, 0.41; 95% CI, 0.24 to 0.70; P<0.001) compared with all other patients. This finding was confirmed in EVEREST (multivariable HR, 0.52; 95% CI, 0.33 to 0.82; P=0.004) for patients with favorable diuretic response and hemoconcentration compared with all other patients. CONCLUSIONS: Combining 2 indicators of decongestion, hemoconcentration and diuretic response improves risk prediction for early rehospitalization after an admission for acute HF and may provide clinicians with an easily accessible tool to identify low-risk patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00354458 and NCT00071331.

Discovery and characterization of GSK256073, a non-flushing hydroxy-carboxylic acid receptor 2 (HCA2) agonist.

Niacin has been used for many years in the treatment of dyslipidemia due to its ability to decrease serum levels of triglycerides and low-density lipoprotein cholesterol and to increase levels of high density lipoprotein cholesterol. However, niacin causes severe flushing resulting in poor patient compliance. The discovery of hydroxy-carboxylic acid receptor 2 (HCA2) as a high affinity receptor for niacin has opened avenues to investigate the mechanism of action of niacin, and to potentially discover agonists which maintain the antilipolytic effects of niacin accessed by a decrease in circulating non-esterified fatty acids (NEFA) and thereby perhaps the lipid/lipoprotein effects, but avoid the flushing effects. Here we describe the strategy we implemented to identify such compounds. This approach resulted in the discovery of GSK256073, a highly potent HCA2 agonist, which produced similar NEFA lowering effects to niacin in preclinical models (rat and guinea pig). A guinea pig model was used to predict flushing, via an increase in ear temperature, and GSK256073 was found to have a minimal effect in this model. These preclinical models appeared to be predictive of human response, since in a first-time-in-human study, GSK256073 displayed long lasting NEFA and triglyceride lowering effects in healthy male subjects, which were not associated with flushing. GSK256073 can be used as a pharmacological tool to better understand the role of HCA2 in lipid metabolism.

Safety considerations for patients with epilepsy taking antiepileptic drugs alongside caffeine or other methylxanthine derivatives.

INTRODUCTION: Antiepileptic drugs (AEDs) are widely used for the treatment of epilepsy. However, ∼ 30% of patients do not remain seizure free. It is possible that methylxanthine derivatives (e.g., caffeine and theophylline) may partially account for this outcome. AREAS COVERED: Data on the convulsive activity of methylxanthines are reviewed. The negative impact of caffeine and theophylline (or aminophylline) on the protective activity of classic and newer AEDs is also considered. Case report studies indicate that ingestion of caffeine may increase seizure frequency, which returns to baseline when the consumption of coffee or caffeine-rich drinks is terminated. However, the existing data also provide clinical evidence that caffeine may not be a trigger for precipitation of seizure activity and this discrepancy is evaluated. EXPERT OPINION: Experimental data indicate that caffeine and aminophylline both significantly reduce the anticonvulsant activity of a number of AEDs. Clinical data are controversial. Patients with epilepsy should be advised not to take methylxanthine-containing medications. Caffeine consumption, especially accidental and in huge quantities, should be avoided in patients with epilepsy.

International differences in clinical characteristics, management, and outcomes in acute heart failure patients: better short-term outcomes in patients enrolled in Eastern Europe and Russia in the PROTECT trial.

AIMS: The implications of geographical variation are unknown following adjustment for hospital length of stay (LOS) in heart failure (HF) trials that included patients whether or not they had systolic dysfunction. We investigated regional differences in an international acute HF trial. METHODS AND RESULTS: The PROTECT trial investigated 2033 patients with acute HF and renal dysfunction hospitalized at 173 sites in 17 countries with randomization to rolofylline or placebo. We grouped enrolling countries into six regions. Baseline characteristics, in-hospital management, and outcomes were explored by region. The primary study outcome was 60-day mortality or cardiovascular/renal hospitalization. Secondary outcomes included 180-day mortality. Of 2033 patients, 33% were from Eastern Europe, 19% from Western Europe, 16% from Israel, 15% from North America, 14% from Russia, and 3% from Argentina. Marked differences in baseline characteristics, HF phenotype, in-hospital diuretic and vasodilator strategies, and LOS were observed by region. LOS was shortest in North America and Israel (median 5 days) and longest in Russia (median 15 days). Regional event rates varied significantly. Following multivariable adjustment, region was an independent predictor of the risk of mortality/hospitalization at 60 days, with the lowest risk in Russia (hazard ratio 0.39, 95% confidence interval 0.23-0.64 vs. Western Europe) due to lower rehospitalization; mortality differences were attenuated by 180 days. CONCLUSIONS: In an international HF trial, there were differences in baseline characteristics, treatments, LOS, and rehospitalization amongst regions, but little difference in longer term mortality. Rehospitalization differences exist independent of LOS. This analysis may help inform future trial design and should be externally validated.

Methylxanthines do not affect rhythmogenic preBötC inspiratory network activity but impair bursting of preBötC-driven motoneurons.

Clinical stimulation of preterm infant breathing with methylxanthines like caffeine and theophylline can evoke seizures. It is unknown whether underlying neuronal hyperexcitability involves the rhythmogenic inspiratory active pre-Bötzinger complex (preBötC) in the brainstem or preBötC-driven motor networks. Inspiratory-related preBötC interneuronal plus spinal (cervical/phrenic) or cranial hypoglossal (XII) motoneuronal bursting was studied in newborn rat en bloc brainstem-spinal cords and brainstem slices, respectively. Non-respiratory bursting perturbed inspiratory cervical nerve activity in en bloc models at >0.25mM theophylline or caffeine. Rhythm in the exposed preBötC of transected en bloc preparations was less perturbed by 10mM theophylline than cervical root bursting which was more affected than phrenic nerve activity. In the preBötC of slices, even 10mM methylxanthine did not evoke seizure-like bursting whereas >1mM masked XII rhythm via large amplitude 1-10Hz oscillations. Blocking A-type γ-aminobutyric (GABAA) receptors evoked seizure-like cervical activity whereas in slices neither XII nor preBötC rhythm was disrupted. Methylxanthines (2.5-10mM), but not blockade of adenosine receptors, phosphodiesterase-4 or the sarcoplasmatic/endoplasmatic reticulum ATPase countered inspiratory depression by muscimol-evoked GABAA receptor activation that was associated with a hyperpolarization and input resistance decrease silencing preBötC neurons in slices. The latter blockers did neither affect preBötC or cranial/spinal motor network bursting nor evoke seizure-like activity or mask corresponding methylxanthine-evoked discharges. Our findings show that methylxanthine-evoked hyperexcitability originates from motor networks, leaving preBötC activity largely unaffected, and suggest that GABAA receptors contribute to methylxanthine-evoked seizure-like perturbation of spinal motoneurons whereas non-respiratory XII motoneuron oscillations are of different origin.

[Clinical and endoscopic characteristics of changes in the esophagogastroduodenal zone in patients with asthma].

The aim of research was to study the frequency and character of clinical-endoscopial disturbances in gastroduodenal zone at 140 BA patients at different regimen of GKS therapy. The high frequency of GERD in BA patients at GKS therapy was established. The dependence of main respiratory simptoms of BA on GEFR, the intencity of cough and dyspnea were found out. Presence of GEFR at BA patients deteriorates patency of airways.

Pharmacology and therapeutics of bronchodilators.

Bronchodilators are central in the treatment of of airways disorders. They are the mainstay of the current management of chronic obstructive pulmonary disease (COPD) and are critical in the symptomatic management of asthma, although controversies around the use of these drugs remain. Bronchodilators work through their direct relaxation effect on airway smooth muscle cells. at present, three major classes of bronchodilators, ß(2)-adrenoceptor (AR) agonists, muscarinic receptor antagonists, and xanthines are available and can be used individually or in combination. The use of the inhaled route is currently preferred to minimize systemic effects. Fast- and short-acting agents are best used for rescue of symptoms, whereas long-acting agents are best used for maintenance therapy. It has proven difficult to discover novel classes of bronchodilator drugs, although potential new targets are emerging. Consequently, the logical approach has been to improve the existing bronchodilators, although several novel broncholytic classes are under development. An important step in simplifying asthma and COPD management and improving adherence with prescribed therapy is to reduce the dose frequency to the minimum necessary to maintain disease control. Therefore, the incorporation of once-daily dose administration is an important strategy to improve adherence. Several once-daily ß(2)-AR agonists or ultra-long-acting ß(2)-AR-agonists (LABAs), such as indacaterol, olodaterol, and vilanterol, are already in the market or under development for the treatment of COPD and asthma, but current recommendations suggest the use of LABAs only in combination with an inhaled corticosteroid. In addition, some new potentially long-acting antimuscarinic agents, such as glycopyrronium bromide (NVA-237), aclidinium bromide, and umeclidinium bromide (GSK573719), are under development, as well as combinations of several classes of long-acting bronchodilator drugs, in an attempt to simplify treatment regimens as much as possible. This review will describe the pharmacology and therapeutics of old, new, and emerging classes of bronchodilator.

The safety of an adenosine A(1)-receptor antagonist, rolofylline, in patients with acute heart failure and renal impairment: findings from PROTECT.

BACKGROUND: Adenosine exerts actions in multiple organ systems, and adenosine receptors are a therapeutic target in many development programmes. OBJECTIVE: The aim of this analysis was to evaluate the safety of rolofylline, an adenosine A(1)-receptor antagonist, in patients with acute heart failure. METHODS: The effect of rolofylline was investigated in patients hospitalized for acute heart failure with impaired renal function. Intravenous rolofylline 30 mg or placebo was infused over 4 hours daily for up to 3 days. Adverse events (AEs) and serious AEs (SAEs) were recorded from baseline through 7 and 14 days, respectively, and clinical events were adjudicated through 60 days. RESULTS: Of 2033 patients enrolled, 2002 received study drug randomized 2 : 1 to rolofylline or placebo. Rolofylline and placebo were associated with a similar risk of pre-specified groups of AEs or SAEs, other than selected neurological events. Investigator-reported seizures occurred in 11 (0.8%) rolofylline-treated patients and zero patients receiving placebo (p = 0.02). Stroke occurred in 21 (1.6%) patients assigned to rolofylline compared with 3 (0.5%) placebo-treated patients through 60 days with a greater risk for stroke in the rolofylline group (hazard ratio 3.49; 95% CI 1.04, 11.71; p = 0.043). There was no temporal relation to rolofylline administration and no specific stroke subtype or clinical characteristics that predicted stroke in the rolofylline group. CONCLUSIONS: Rolofylline treatment was associated with an increased seizure rate, an anticipated complication of A(1)-receptor antagonists. An unanticipated, disproportionate increase in strokes in the rolofylline-treated patients emerged, although no clear temporal relation, aetiology, stroke subtype or interacting factor suggestive of a causal mechanism was identified. Further research into stroke as a potential complication of adenosine-modulating therapies is required. Additionally, this study underscores the value of longer follow-up durations for AEs, even for agents with short treatment periods, such as in acute heart failure.