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Mario Cazzola,1 Nicola A Hanania,2 Clive P Page,3 Maria Gabriella Matera4 1Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy; 2Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 3Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, London, UK; 4Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, ItalyCorrespondence: Mario Cazzola, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy, Email mario.cazzola@uniroma2.itAbstract: Airway inflammation, driven by different types of inflammatory cells and mediators, plays a fundamental role in COPD and its progression. Neutrophils, eosinophils, macrophages, and CD4+ and CD8+ T lymphocytes are key players in this process, although the extent of their participation varies according to the patient’s endotype. Anti-inflammatory medications may modify the natural history and progression of COPD. However, since airway inflammation in COPD is relatively resistant to corticosteroid therapy, innovative pharmacological anti-inflammatory approaches are required. The heterogeneity of inflammatory cells and mediators in annethe different COPD endo-phenotypes requires the development of specific pharmacologic agents. Indeed, over the past two decades, several mechanisms that influence the influx and/or activity of inflammatory cells in the airways and lung parenchyma have been identified. Several of these molecules have been tested in vitro models and in vivo in laboratory animals, but only a few have been studied in humans. Although early studies have not been encouraging, useful information emerged suggesting that some of these agents may need to be further tested in specific subgroups of patients, hopefully leading to a more personalized approach to treating COPD.Keywords: anti-inflammatory drugs, COPD, inflammation, treatment

Mario Cazzola,1 Paola Rogliani,1 Rossella Laitano,1 Luigino Calzetta,2 Maria Gabriella Matera3 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy; 2Unit of Respiratory Diseases and Lung Function, Department of Medicine and Surgery, University of Parma, Parma, Italy; 3Unit of Pharmacology, Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, ItalyCorrespondence: Mario Cazzola Email mario.cazzola@uniroma2.itAbstract: Although pharmacological treatment of COPD is codified in different guidelines and strategy documents, there is abundant evidence of discrepancy between what they suggest and what health professionals prescribe, especially in low-risk groups where there is widespread overprescription of triple therapy. It is therefore necessary to clarify when the use of triple therapy is indicated in COPD patients and when it is preferable to maintain treatment with dual bronchodilation. In this article, we discuss our views based on our experience and what is reported in the literature and try to give answers to these two questions. The evidence generated by pivotal RCTs supports the use of triple therapy in patients who present for the first time and have severe airway obstruction, are symptomatic, have had frequent moderate or severe exacerbations in the previous year, and have peripheral eosinophilia. However, it is difficult to determine whether step-up is useful in all other cases because the available data are quite conflicting. It is likely that the inconsistency in the information generated by the various available studies may explain the prescribing behaviour of many physicians who do not adhere to recommendations of guidelines and strategies. However, it is necessary to establish whether and when the addition of an ICS to the LAMA/LABA combination is effective, to determine whether triple therapy can induce an additional clinical benefit over dual bronchodilation, irrespective of a preventive effect on COPD exacerbations, to establish its value, and to examine whether cost differences can support the use of triple therapy over combined LAMA/LABA therapy in real life.Keywords: dual bronchodilation, triple therapy, ICSs, LABs, LAMAs

Mario Cazzola,1 Josuel Ora,2 Francesco Cavalli,1 Paola Rogliani,1,2 Maria Gabriella Matera3 1Chair of Respiratory Medicine, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy; 2Division of Respiratory Medicine, University Hospital Tor Vergata, Rome, Italy; 3Chair of Pharmacology, Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, ItalyCorrespondence: Mario Cazzola Email mario.cazzola@uniroma2.itAbstract: Several mAbs have been tested or are currently under clinical evaluation for the treatment of COPD. They can be subdivided into those that aim to block specific pro-inflammatory and pro-neutrophilic cytokines and chemokines, such as TNF-α, IL-1β, CXCL8 and IL-1β, and those that act on T2-mediated inflammation, respectively, by blocking IL-5 and/or its receptor, preventing IL-4 and IL-13 signaling, affecting IL-33 pathway and blocking TSLP. None of these approaches has proved to be effective, probably because in COPD there is no dominant cytokine or chemokine and, therefore, a single mAb cannot be effective on all pathways. With a more in-depth understanding of the numerous pheno/endotypic pathways that play a role in COPD, it may eventually be possible to identify those specific patients in whom some of these cytokines or chemokines might predominate. In this case, it will be possible to implement a personalized treatment, but the use of each mAb will only be reserved for a very limited number of subjects.Keywords: COPD, monoclonal antibodies, pheno/endotypic pathways, anti–T1-mediated inflammation mAbs, anti–T2-mediated inflammation mAbs

Maria Gabriella Matera,1 Josuel Ora,2 Francesco Cavalli,2 Paola Rogliani,2,3 Mario Cazzola3 1Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy; 2Respiratory Diseases Unit, “Tor Vergata” University Hospital, Rome, Italy; 3Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, ItalyCorrespondence: Mario CazzolaDipartimento di Medicina Sperimentale, Università di Roma Tor Vergata, Rome, ItalyEmail mario.cazzola@uniroma2.itIntroduction: Phosphodiesterases (PDEs) are isoenzymes ubiquitously expressed in the lungs where they catalyse cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (GMP), which are fundamental second messengers in asthma, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signaling pathways and, consequently, myriad biological responses. The superfamily of PDEs is composed of 11 families with a distinct substrate specificity, molecular structure and subcellular localization. Experimental studies indicate a possible role in asthma mainly for PDE3, PDE4, PDE5 and PDE7. Consequently, drugs that inhibit PDEs may offer novel therapeutic options for the treatment of this disease.Areas Covered: In this article, we describe the progress made in recent years regarding the possibility of using PDE inhibitors in the treatment of asthma.Expert Opinion: Many data indicate the potential benefits of PDE inhibitors as an add-on treatment especially in severe asthma due to their bronchodilator and/or anti-inflammatory activity, but no compound has yet reached the market as asthma treatment mainly because of their limited tolerability. Therefore, there is a growing interest in developing new PDE inhibitors with an improved safety profile. In particular, the research is focused on the development of drugs capable of interacting simultaneously with different PDEs, or to be administered by inhalation. CHF 6001 and RPL554 are the only molecules that currently are under clinical development but there are several new agents with interesting pharmacological profiles. It will be stimulating to assess the impact of such agents on individual treatable traits in specially designed studies.Keywords: asthma, phosphodiesterases, phosphodiesterase inhibitors, bifunctional drugs, treatable traits therapeutic approach

Mario Cazzola,1 Paola Rogliani,1 Luigino Calzetta,2 Maria Gabriella Matera3 1Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy; 2Unit of Respiratory Disease and Lung Function, Department of Medicine and Surgery, University of Parma, Parma, Italy; 3Unit of Pharmacology, Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, ItalyCorrespondence: Mario Cazzola Email mario.cazzola@uniroma2.itAbstract: There is a large interindividual variability in response to ICSs in asthma. About 70% of the variance in ICS response is likely due at least partially to genetically determined characteristics of target genes. In this article, we examine the effects on the ICS response of gene variations in the corticosteroid pathway, and in the pharmacokinetics of corticosteroids, and also those outside the corticosteroid pathway, which have the potential to influence corticosteroid activity. Although the available evidence indicates that responses to ICSs in asthma are influenced by different genetic variants, there are still deep uncertainties as to whether a real association between these genetic variants and corticosteroid response could also possibly exist because there are difficulties in reproducing pharmacogenetic findings. This explains at least partly the insufficient use of pharmacogenomic data when treating asthmatic patients, which creates a real limitation to the proper use of ICSs in an era of precision medicine that links the right patient to the right treatment. Knowing and dealing with the genetic factors that influence the therapeutic ICS response is a fundamental condition for prescribing the right dose of ICS to the right patient at the right time.Keywords: asthma, inhaled corticosteroids, gene polymorphisms, genome-wide association studies, precision medicine

Paola Rogliani,1,2 Maria Gabriella Matera,3 Josuel Ora,2 Mario Cazzola,1 Luigino Calzetta1 1Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy; 2Division of Respiratory Medicine, University Hospital Tor Vergata, Rome, Italy; 3Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy Objective: Long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are burdened by the potential risk of inducing cardiovascular serious adverse events (SAEs) in COPD patients. Since the risk of combining a LABA with a LAMA could be greater, we have carried out a quantitative synthesis to investigate the cardiovascular safety profile of LABA/LAMA fixed-dose combinations (FDCs).Methods: A pair-wise and network meta-analysis was performed by using the data of the repository database ClinicalTrials.gov concerning the impact of approved LABA/LAMA FDCs versus monocomponents and/or placebo on cardiovascular SAEs in COPD.Results: Overall, LABA/LAMA FDCs did not significantly (P>0.05) modulate the risk of cardiovascular SAEs versus monocomponents. However, the network meta-analysis indicated that aclidinium/formoterol 400/12 µg and tiotropium/olodaterol 5/5 µg were the safest FDCs, followed by umeclidinium/vilanterol 62.5/25 µg which was as safe as placebo, whereas glyco­pyrronium/formoterol 14.9/9.6, glycopyrronium/indacaterol 15.6/27.5 µg, and glycopyrronium/indacaterol 50/110 µg were the least safe FDCs. No impact on mortality was detected for each specific FDC.Conclusion: This meta-analysis indicates that LABA/LAMA FDC therapy is characterized by an excellent cardiovascular safety profile in COPD patients. However, the findings of this quantitative synthesis have been obtained from populations that participated in randomized clinical trials, and were devoid of major cardiovascular diseases. Thus, post-marketing surveillance and observational studies may help to better define the real impact of specific FDCs with regard to the cardiovascular risk. Keywords: COPD, LABA/LAMA FDC, cardiovascular safety, mortality, meta-analysis

Maria Gabriella Matera,1 Clive Page,2 Mario Cazzola3 1Department of Experimental Medicine, Unit of Pharmacology, University of Campania ‘Luigi Vanvitelli’, Naples, Italy; 2Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, London, UK; 3Department of Experimental Medicine and Surgery, Chair of Respiratory Medicine, University of Rome ‘Tor Vergata’, Rome, Italy Abstract: 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 β2-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. Keywords: doxofylline, theophylline, mechanisms of action, therapeutic effects, adverse effects

Maria Gabriella Matera,1 Alessandro Sanduzzi,2 Mario Cazzola3 1Department of Experimental Medicine, Second University of Naples, 2Department of Respiratory Diseases, Monaldi Hospital, University Federico II, Naples, 3Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy Abstract: Co-administration of a long-acting β2-agonist and a long acting muscarinic antagonist produces superior bronchodilation compared with their individual effects. Our preclinical data indicated that combining aclidinium bromide (ACLI) and formoterol fumarate (FORM) provides synergistic benefit on smooth muscle relaxation of both large and small human airways. Data from more than 2,000 patients in eleven clinical trials documented that ACLI/FORM, a twice-daily fixed-dose combination, produces a greater degree of bronchodilation than ACLI or FORM monotherapy alone and is safe and well tolerated. Two large key trials have shown that there is a benefit in using ACLI/FORM when the clinical target is the variability of symptoms and mainly nighttime and/or early morning symptoms. ACLI/FORM is the only long acting muscarinic antagonist/long acting β2-agonist fixed-dose combination that has been studied for this therapeutic indication. Keywords: aclidinium, formoterol, fixed-dose combination, COPD, symptoms

Maria Gabriella Matera,1 Josuel Ora,2 Mario Cazzola2,3 1Department of Experimental Medicine, Unit of Pharmacology, Second University of Naples, Naples, 2Division of Respiratory Medicine, University Hospital Tor Vergata, 3Department of Systems Medicine, Respiratory Pharmacology Research Unit, University of Rome Tor Vergata, Rome, Italy Abstract: Olodaterol (BI 1744 CL) is a novel, once-daily long-acting β2-agonist (LABA) designed with the aim of improving β2-adrenoreceptor selectivity and intrinsic activity. Phase III pivotal trials have documented that olodaterol Respimat Soft Mist inhaler 5 µg induces fast onset of bronchodilation, comparable with formoterol at day 1. Moreover, significant lung function improvements have been documented up to 48 weeks in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). Olodaterol was generally well tolerated and had an acceptable cardiovascular and respiratory adverse event profile. Regrettably, the clinical development of olodaterol is however still too partial to draw any firm conclusions on the positioning of this ultra-LABA as monotherapy in the management of COPD. Waiting for further data on the impact of olodaterol on different patient-reported outcomes, which however are widely available for indacaterol, and mainly for a head-to-head comparison between these two ultra-LABAs and between olodaterol long-acting antimuscarinic antagonists other than tiotropium, we believe it is correct to follow the clinical indications of indacaterol also for olodaterol. In any case, the parallel bronchodilating modes of action of olodaterol and tiotropium make them an attractive combination in COPD. The results from the ongoing large TOviTO Phase III trial program have documented the efficacy and safety of olodaterol/tiotropium fixed-dose combination as maintenance therapy in patients with moderate to very severe COPD. In particular, olodaterol/tiotropium fixed-dose combination provides a convincing alternative for patients remaining symptomatic with olodaterol monotherapy. Keywords: olodaterol, β2-agonists, once-daily dose, chronic obstructive pulmonary disease

Rogliani P, Matera MG, Ora J, Cazzola M, Calzetta L. International Journal of Chronic Obstructive Pulmonary Disease. 2017; 12:3469—3485. Page 3481, right column, last paragraph, line 3, the text “(fromoterol and indacaterol)” should read “(formoterol and indacaterol)”. Read the original article

Mario Cazzola,1 Andrea Segreti,1 Maria Gabriella Matera2 1Department of System Medicine, University of Rome 'Tor Vergata', Rome, Italy; 2Department of Experimental Medicine, Second University, Naples, Italy Abstract: An increasing body of evidence suggests that the long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combination appears to play an important role in maximizing bronchodilation, with studies to date indicating that combining different classes of bronchodilators may result in significantly greater improvements in lung function compared to the use of a single drug, and that these combinations are well tolerated in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). An inhaled, fixed-dose combination of two 24-hour bronchodilators, the LAMA umeclidinium and the LABA vilanterol, is under development as a once-daily treatment for COPD. The efficacy of both mono-components has already been demonstrated. The information currently available suggests that umeclidinium/vilanterol is an effective once-daily dual bronchodilator fixed-dose combination in the treatment of COPD. However, it remains to be seen if it compares favorably with current therapies. Moreover, the question remains whether umeclidinium/vilanterol fixed-dose combination, which significantly improves FEV1, is also associated with improvements in other outcome measures that are important to COPD patients. Keywords: muscarinic antagonist, dual bronchodilation, COPD

Abstract Background Increasing clinical epidemiological and experimental evidence indicates that excess of production of reactive oxygen free radicals (ROS) induced by an oxidative stress is involved in the pathogenesis of a number of human airway disorders, as well as equine recurrent airway obstruction. Free-radicals modulate the activation of transcription factors, such as nuclear factor-(NF)-κB and activator protein (AP)-1, in several different cells. This activation leads to expression of many pro-inflammatory cytokines, including interleukin (IL)-1β. We have hypothesized that equine airway sensitization might induce an oxidative stress and increase the ROS production, which in turn might enhance a production of IL-1β and airway hyperresponsiveness. Methods We have examined the effect of passive sensitization on IL-1β mRNA expression and electrical field stimulation (EFS)-induced contraction in equine isolated bronchi, and the potential interference of reduced-glutathione (GSH), an antioxidant, with these responses. Bronchi passively sensitized with serum from animals suffering from heaves and having high total level of IgE, and control tissues, either pretreated or not with GSH (100 μM), were used to quantify IL-1β mRNA. Other tissues were used to study the effect of EFS (3–10–25 Hz). Results Mean IL-1β mRNA expression was higher in passively sensitized than in control rings. GSH significantly (p < 0.05) reduced the IL-1β mRNA expression only in passively sensitized bronchi. ELF induced a frequency-dependent contraction in both non-sensitized and passively sensitized tissues, with a significantly greater response always observed in sensitized tissues. GSH did not modify the EFS-induced contraction in non-sensitized bronchi, but significantly (p < 0.05) decreased it in passively sensitized tissues. Conclusion Our data indicate that the passive sensitization of equine bronchi induces inflammation and hyperresponsiveness. These effects might be due to an oxidative stress because a pretreatment with GSH decreased the increased IL-1β mRNA expression and responsiveness to EFS of passively sensitized bronchi.

Reelin, a serine protease encoded by the RELN gene, is part of the apolipoprotein E (apoE) biochemical pathway that is involved in the pathogenesis of Alzheimer's disease (AD). Sex-related differences in the epidemiology, pathology and clinical characteristics of AD have been reported. To explore the potential contribution of RELN gene variants in the pathogenesis of AD, we investigated three polymorphisms spanning the RELN locus, i.e., a triplet tandem repeat in the 5'UTR and two single-nucleotide polymorphisms (SNPs) rs607755 and rs2229874, located in the splice-junction of exon 6 and in the coding region of exon 50. The analysis was made in 223 sporadic AD patients and 181 age-matched controls of Caucasian ethnicity. Significant differences between AD patients and controls were found in distribution of 5'UTR and rs607755 genotypes, whereas no differences were found in the distribution of rs2229874 genotypes. When patients and controls were divided according to sex, significant differences in genotype distribution were found in females and not in males, also after adjustment for APOE genotypes. These findings suggest that RELN gene variants may play a role in the pathogenesis of AD, particularly in females. [ABSTRACT FROM AUTHOR]

We assessed the role of the APOE genotype and prion protein polymorphism at codon 129 in predicting the clinical duration of 92 neuropathologically confirmed sporadic Alzheimer's disease patients. Analyses of survival showed that the absence of the APOE epsilon 4 allele in heterozygous codon 129 PRNP carriers is a negative predictor of survival. When this subgroup of patients was stratified by sex, the effect of APOE was observed in women, but not in men. [ABSTRACT FROM AUTHOR]

BACKGROUND: The glutamatergic neurotransmitter systems play a crucial role in memory formation and information processing. Alterations in this system contribute to the manifestation of symptoms in Alzheimer's disease (AD). Glutamate transmits signals via the N-methyl-D-aspartate receptors (NMDARs). Aims: The potential involvement of polymorphisms in the GRIN2B gene, encoding subunit 2B of the NMDA receptor, in the risk for AD was evaluated. METHODS: We investigated the 3 single-nucleotide polymorphisms (SNPs) rs1019385, rs1806201 and rs890, i.e. the G(-200)-->T transversion in the 5'UTR, the A(2664)-->G transition in exon 13 and the G(5072)-->T transition in the 3'UTR of the GRIN2B gene, in 222 Caucasian AD patients and 170 healthy Caucasian age-matched controls. RESULTS: No differences were found in the overall distribution of the single-nucleotide polymorphism genotypes between AD patients and healthy controls, even when the analysis was adjusted for sex, age and APOE. As expected from genotype frequencies, no differences were found in the distribution of the estimated allele and haplotype frequencies between AD patients and healthy controls. CONCLUSION: In this study no significant association between polymorphisms in the GRIN2B gene and AD was observed. Further investigations of polymorphisms in the gene encoding the NMDA receptor 2B subunit in AD patients with different genetic setting are needed to clarify their role in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

There has been a real interest recently in developing once-daily beta(2)-adrenoceptor agonists (ultra-long-acting beta(2)-adrenoceptor agonists [ultra-LABAs]) for treating asthma and chronic obstructive pulmonary disease (COPD) in an attempt to simplify their management, although an increasing amount of convincing data show an association of LABAs with a rise in asthma-related deaths and life-threatening experiences. This paper reviews the effects of different ultra-LABAs that are at varying stages of development. Arformoterol, carmoterol, indacaterol and GSK-159797 are ultra-LABAs that are likely to be introduced into the market before 2010. It is plausible that once-daily dose administration of an LABA will lead to increased convenience for patients, which may also lead to enhancement of adherence, and may have advantages leading to improved overall clinical outcomes in patients with asthma and COPD. [ABSTRACT FROM AUTHOR]

We investigated the association of sex and age with the occurrence of apolipoprotein E (apoE) and angiotensin-converting enzyme (ACE) genotypes in healthy aging and longevity in 1344 healthy individuals and 64 centenarians. As compared to participants younger than 60 years, a significant higher frequency of the apoE/epsilon2 was observed in men aged 60-90 years (p <.001) and in centenarians (p <.001). Logistic regression analysis confirmed this outcome in both participants aged 60-90 years (odds ratio [OR] = 1.897; 95% confidence interval [CI], 1.227-2.931) and centenarians (OR = 3.263; 95% CI, 1.860-5.722). A further significant association of ACE/D allele and age was observed in centenarians (OR = 2.135; 95% CI, 1.253-3.636). Heterosis was also observed at the ACE locus. No relationship between apoE and ACE polymorphism was found. These findings suggest a role of sex in the association of apoE and ACE gene polymorphisms with healthy aging and longevity. [ABSTRACT FROM AUTHOR]

Although large surveys have documented the favourable safety profile of beta(2)-adrenoceptor agonists (beta(2)-agonists) and, above all, that of the long-acting agents, the presence in the literature of reports of adverse cardiovascular events in patients with obstructive airway disease must induce physicians to consider this eventuality. The coexistence of beta(1)- and beta(2)-adrenoceptors in the heart clearly indicates that beta(2)-agonists do have some effect on the heart, even when they are highly selective. It should also be taken into account that the beta(2)-agonists utilised in clinical practice have differing selectivities and potencies. beta(2)-agonist use has, in effect, been associated with an increased risk of myocardial infarction, congestive heart failure, cardiac arrest and sudden cardiac death. Moreover, patients who have either asthma or chronic obstructive pulmonary disease may be at increased risk of cardiovascular complications because these diseases amplify the impact of these agents on the heart and, unfortunately, are a confounding factor when the impact of beta(2)-agonists on the heart is evaluated. Whatever the case may be, this effect is of particular concern for those patients with underlying cardiac conditions. Therefore, beta(2)-agonists must always be used with caution in patients with cardiopathies because these agents may precipitate the concomitant cardiac disease. [ABSTRACT FROM AUTHOR]

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (COPD) are managed with increased doses or frequency of the patient's existing bronchodilator therapy. The use of formoterol in the treatment of mild acute exacerbations of COPD has been suggested; however, a comparison of cumulative doses of formoterol with salbutamol, the gold standard bronchodilator agent for this pathologic condition, is still lacking. OBJECTIVE: The aim of the study was to compare the inhaled beta2-agonists salbutamol (rapid onset, short duration of action) and formoterol (rapid onset, long duration of action), both used as needed in patients attending outpatient clinics because of mild acute exacerbations of COPD (Anthonisen exacerbation type I or II). METHODS: A dose-response curve to formoterol via Turbuhaler or salbutamol via pressurized metered-dose inhaler (pMDI) was constructed. On 2 consecutive days, the patients received, in randomized order, both of the following active dose regimens: A = 12 + 12 + 24 microg formoterol via Turbuhaler (48-microg cumulative metered dose); B = 200 + 200 + 400 microg salbutamol via pMDI (800-microg cumulative metered dose). Dose increments were given at 30-minute intervals, with measurements made 25 minutes after each dose. The maximum forced expiratory volume in 1 second (FEV1) value during the dose-response curve to formoterol or salbutamol was chosen as the primary outcome variable to compare the 2 treatments. Oxygen saturation by pulse oximetry (SpO2) and pulse rate were also measured at each assessment period. Every adverse event, either reported spontaneously by the patients or observed by the investigators, was recorded. RESULTS: Sixteen patients (2 women, 14 men) aged 51 to 77 years (most older than 65 years) participated in the study. Both formoterol and salbutamol induced a large, significant, dose-dependent increase in FEV1, inspiratory capacity (IC), and forced vital ca- pacity (FVC). There was no significant difference between FEV1, IC, and FVC values after 48 microg formoterol and 800 microg salbutamol. There was no significant difference in FEV1 after 24 microg formoterol and 800 microg salbutamol; however, the difference in FEV1 after 24 and 48 microg formoterol was significant. Neither heart rate (mean differences from baseline after 48 microg formoterol, 1.9 beats/min [95% CI, -3.4, 7.2] and 800 microg salbutamol, 3.7 beats/min [95% CI, -1.1, 8.5]) nor SpO2 (mean percentage differences from baseline after 48 microg formoterol, -0.37% [95% CI, -1.22, 0.47] and 800 microg salbutamol, -0.75% [95% CI, -1.73, 0.23]) changed significantly. However, SpO2 decreased below 90% in 2 patients after the highest dose of formoterol and in 1 patient after the highest dose of salbutamol. CONCLUSIONS: In this small, selected group of patients with mild acute exacerbations of COPD, formoterol via Turbuhaler induced a fast bronchodilation that was dose dependent and not significantly different from that caused by salbutamol. Furthermore, formoterol appeared to be as well tolerated as salbutamol. [ABSTRACT FROM AUTHOR]