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Concept: Theophylline

15

One may wonder why methylxanthines are so abundant in beverages used by humans for centuries, or in cola-drinks that have been heavily consumed since their appearance. It is likely that humans have stuck to any brew containing compounds with psychoactive properties, resulting in a better daily life, i.e., more efficient thinking, exploring, hunting, etc., however, without the serious side effects of drugs of abuse. The physiological effects of methylxanthines have been known for a long time and they are mainly mediated by the so-called adenosine receptors. Caffeine and theobromine are the most abundant methylxanthines in cacao and their physiological effects are notable. Their health-promoting benefits are so remarkable that chocolate is explored as a functional food. The consequences of adenosine receptor blockade by natural compounds present in cacao/chocolate are here reviewed. Palatability and health benefits of methylxanthines, in general, and theobromine, in particular, have further contributed to sustain one of the most innocuous and pleasant habits: chocolate consumption.

Concepts: Caffeine, Adenosine receptor, Phosphodiesterase inhibitor, Adenosine, Chocolate, Xanthine, Theobromine, Theophylline

12

Health professionals tasked with advising patients with asthma and chronic obstructive pulmonary disease (COPD) how to use inhaler devices properly and what to do about unwanted effects will be aware of a variety of commonly held precepts. The evidence for many of these is, however, lacking or old and therefore in need of re-examination. Few would disagree that facilitating and encouraging regular and proper use of inhaler devices for the treatment of asthma and COPD is critical for successful outcomes. It seems logical that the abandonment of unnecessary or ill-founded practices forms an integral part of this process: the use of inhalers is bewildering enough, particularly with regular introduction of new drugs, devices and ancillary equipment, without unnecessary and pointless adages. We review the evidence, or lack thereof, underlying ten items of inhaler ‘lore’ commonly passed on by health professionals to each other and thence to patients. The exercise is intended as a pragmatic, evidence-informed review by a group of clinicians with appropriate experience. It is not intended to be an exhaustive review of the literature; rather, we aim to stimulate debate, and to encourage researchers to challenge some of these ideas and to provide new, updated evidence on which to base relevant, meaningful advice in the future. The discussion on each item is followed by a formal, expert opinion by members of the ADMIT Working Group.

Concepts: Critical thinking, Asthma, Chronic obstructive pulmonary disease, Pulmonary hypertension, Spirometry, Inhaler, Theophylline, Ipratropium

7

Caffeine reduces toxic Ca(2+) signals in pancreatic acinar cells via inhibition of inositol 1,4,5-trisphosphate receptor (IP3R)-mediated signalling, but effects of other xanthines have not been evaluated, nor effects of xanthines on experimental acute pancreatitis (AP). We have determined effects of caffeine and its xanthine metabolites on pancreatic acinar IP3R-mediated Ca(2+) signalling and experimental AP.

Concepts: Pancreas, Caffeine, Xanthine, Theobromine, Theophylline

6

There is limited information on the causes of death in asthma patients.Objectives: To determine the causes of death in hospitalized asthmatic patients and to compare with those observed in COPD patients and non-respiratory individuals, with a particular interest in associations with previous cardiovascular disease.

Concepts: Immune system, Disease, Diseases and disorders, Asthma, Chronic obstructive pulmonary disease, Bronchodilator, Theophylline, Ipratropium

4

Errors in the use of different inhalers were investigated in patients naive to the devices under investigation in a multicentre, single-visit, randomised, open-label, cross-over study. Patients with chronic obstructive pulmonary disease (COPD) or asthma were assigned to ELLIPTA vs DISKUS (Accuhaler), metered-dose inhaler (MDI) or Turbuhaler. Patients with COPD were also assigned to ELLIPTA vs Handihaler or Breezhaler. Patients demonstrated inhaler use after reading the patient information leaflet (PIL). A trained investigator assessed critical errors (i.e., those likely to result in the inhalation of significantly reduced, minimal or no medication). If the patient made errors, the investigator demonstrated the correct use of the inhaler, and the patient demonstrated inhaler use again. Fewer COPD patients made critical errors with ELLIPTA after reading the PIL vs: DISKUS, 9/171 (5%) vs 75/171 (44%); MDI, 10/80 (13%) vs 48/80 (60%); Turbuhaler, 8/100 (8%) vs 44/100 (44%); Handihaler, 17/118 (14%) vs 57/118 (48%); Breezhaler, 13/98 (13%) vs 45/98 (46%; all P<0.001). Most patients (57-70%) made no errors using ELLIPTA and did not require investigator instruction. Instruction was required for DISKUS (65%), MDI (85%), Turbuhaler (71%), Handihaler (62%) and Breezhaler (56%). Fewer asthma patients made critical errors with ELLIPTA after reading the PIL vs: DISKUS (3/70 (4%) vs 9/70 (13%), P=0.221); MDI (2/32 (6%) vs 8/32 (25%), P=0.074) and significantly fewer vs Turbuhaler (3/60 (5%) vs 20/60 (33%), P<0.001). More asthma and COPD patients preferred ELLIPTA over the other devices (all P⩽0.002). Significantly, fewer COPD patients using ELLIPTA made critical errors after reading the PIL vs other inhalers. More asthma and COPD patients preferred ELLIPTA over comparator inhalers.

Concepts: Asthma, Patient, Chronic obstructive pulmonary disease, Metered-dose inhaler, Dry powder inhaler, Inhaler, Nebulizer, Theophylline

4

BACKGROUND: Respiratory irritants represent a major cause of occupational obstructive airway diseases. We provide an overview of the evidence related to irritative agents causing occupational asthma or occupational COPD. METHODS: We searched MEDLINE via PubMed. Reference lists of relevant reviews were also screened. The SIGN grading system was used to rate the quality of each study. The modified RCGP three-star system was used to grade the body of evidence for each irritant agent regarding its causative role in either occupational asthma or occupational COPD. RESULTS: A total of 474 relevant papers were identified, covering 188 individual agents, professions or work-sites. The focus of most of the studies and the predominant diagnosis was occupational asthma, whereas occupational COPD arose only incidentally.The highest level assigned using the SIGN grading was 2+ (well-conducted systematic review, cohort or case–control study with a low risk of confounding or bias). According to the modified RCGP three-star grading, the strongest evidence of association with an individual agent, profession or work-site (“**”) was found for 17 agents or work-sites, including benzene-1,2,4-tricarboxylicacid-1,2-anhydride, chlorine, platinum salt, isocyanates, cement dust, grain dust, animal farming, environmental tobacco smoke, welding fumes or construction work. Phthalic anhydride, glutaraldehyde, sulphur dioxide, cotton dust, cleaning agents, potrooms, farming (various), foundries were found to be moderately associated with occupational asthma or occupational COPD (“*[+]”). CONCLUSION: This study let us assume that irritant-induced occupational asthma and especially occupational COPD are considerably underreported. Defining the evidence of the many additional occupational irritants for causing airway disorders will be the subject of continued studies with implications for diagnostics and preventive measures.

Concepts: Asthma, Smoking, Tobacco smoking, Chronic obstructive pulmonary disease, Obstructive lung disease, Occupational asthma, Bronchodilator, Theophylline

2

The adenosine A1 and A2A receptors belong to the purinergic family of G protein-coupled receptors, and regulate diverse functions of the cardiovascular, respiratory, renal, inflammation, and CNS. Xanthines such as caffeine and theophylline are weak, non-selective antagonists of adenosine receptors. Here we report the structure of a thermostabilized human A1 receptor at 3.3 Å resolution with PSB36, an A1-selective xanthine-based antagonist. This is compared with structures of the A2A receptor with PSB36 (2.8 Å resolution), caffeine (2.1 Å), and theophylline (2.0 Å) to highlight features of ligand recognition which are common across xanthines. The structures of A1R and A2AR were analyzed to identify the differences that are important selectivity determinants for xanthine ligands, and the role of T270(7.35) in A1R (M270(7.35) in A2AR) in conferring selectivity was confirmed by mutagenesis. The structural differences confirmed to lead to selectivity can be utilized in the design of new subtype-selective A1R or A2AR antagonists.

Concepts: Signal transduction, Receptor, Receptor antagonist, Metabotropic glutamate receptor, Caffeine, Adenosine receptor, Xanthine, Theophylline

2

Various studies have explored different ways to speed emergence from anesthesia. Previously, we have shown that three drugs that elevate intracellular cAMP (forskolin, theophylline and caffeine) accelerate emergence from anesthesia in rats. However, our earlier studies left two main questions unanswered. First, were cAMP elevating drugs effective at all anesthetic concentrations? Second, given that caffeine was the most effective of the drugs tested, why was caffeine more effective than forskolin since both drugs elevate cAMP? In our current study, emergence time from anesthesia was measured in adult rats exposed to 3% isoflurane for 60 minutes. Caffeine dramatically accelerated emergence from anesthesia, even at the high level of anesthetic employed. Caffeine has multiple actions including blockade of adenosine receptors. We show that the selective A2a adenosine receptor antagonist preladenant or the [cAMP]i-elevating drug forskolin, accelerated recovery from anesthesia. When preladenant and forskolin were tested together, the effect on anesthesia recovery time was additive indicating that these drugs operate via different pathways. Furthermore, the combination of preladenant and forskolin was about as effective as caffeine suggesting that both A2A receptor blockade and [cAMP]i elevation play a role in caffeine’s ability to accelerate emergence from anesthesia. Because anesthesia in rodents is thought to be similar to that in humans, these results suggest that caffeine might allow for rapid and uniform emergence from general anesthesia in humans at all anesthetic concentrations and that both the elevation of [cAMP]i and adenosine receptor blockade play a role in this response.

Concepts: Receptor, Receptor antagonist, Caffeine, Adenosine receptor, Adenosine, Adenosine A2A receptor, Adenosine A1 receptor, Theophylline

1

Optimizing the management of children presenting with acute severe asthma is of utmost importance to minimize hospital stays, morbidity, and mortality. Intravenous medications, including theophyllines, are used as second-line treatments for children experiencing a life-threatening exacerbation. For intravenous theophylline (aminophylline), guidelines and formularies recommend a target therapeutic range between 10 and 20 mg/l, with the commonest regimen being a loading dose of 5 mg/kg followed by an infusion calculated by age and weight. This review assesses the evidence underpinning these recommendations, highlighting the shortcomings in our understanding of the association between serum concentrations achieved, dose given, and clinical improvement experienced. To close the knowledge gap and improve outcomes for children presenting with acute severe asthma, we propose a series of research strategies to improve the assessment of illness severity, ascertain the optimal dose to maximize benefit and minimize risk, prospectively collect adverse events, and to better understand the inter-individual variation in responses to treatments.

Concepts: Better, Pharmacology, Asthma, Optimization, Maxima and minima, Theophylline

1

Asthma and chronic obstructive pulmonary disease (COPD) are common airway diseases. Individuals with overlapping asthma and COPD experience increased health impairment and severe disease exacerbations. Efficacious treatment options are required for this population. Omalizumab (anti-IgE) therapy is effective in patients with severe, persistent asthma, but limited data are available on efficacy in populations with overlapping asthma and COPD.

Concepts: Medicine, Asthma, Demography, Chronic obstructive pulmonary disease, Spirometry, Obstructive lung disease, Theophylline, Ipratropium