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Donald P Tashkin,1 Nicholas J Gross2 1Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 2Department of Medicine, University Medical Research LLC, Saint Francis Hospital and Medical Center, Hartford, CT, USA Abstract: Long-acting muscarinic antagonists (LAMAs), along with long-acting β2-agonists (LABAs), are the mainstay for treatment of patients with COPD. Glycopyrrolate, or glycopyrronium bromide, like other LAMAs, inhibits parasympathetic nerve impulses by selectively blocking the binding of acetylcholine to muscarinic receptors. Glycopyrrolate is unusual in that it preferentially binds to M3 over M2 muscarinic receptors, thereby specifically targeting the primary muscarinic receptor responsible for bronchoconstriction occurring in COPD. Inhaled glycopyrrolate is slowly absorbed from the lungs and rapidly eliminated from the bloodstream, most likely by renal excretion in its unmetabolized form, limiting the potential for systemic adverse events. Inhaled glycopyrrolate is a fast-acting, efficacious treatment option for patients with moderate–severe COPD. It improves lung function, reduces the risk of exacerbations, and alleviates the symptoms of breathlessness, which in turn may explain the improvement seen in patients’ quality of life. Inhaled formulations containing glycopyrrolate are well tolerated, and despite being an anticholinergic, few cardiovascular-related events have been reported. Inhaled glycopyrrolate is thus of value as both monotherapy and in combination with other classes of medication for maintenance treatment of COPD. This review covers the mechanism of action of inhaled glycopyrrolate, including its pharmacokinetic, pharmacodynamic, and safety profiles, and effects on mucus secretion. It also discusses the use of inhaled glycopyrrolate in the treatment of COPD, as monotherapy and in fixed-dose combinations with LABAs and inhaled corticosteroid–LABAs, including a triple therapy recently approved in Europe. Keywords: glycopyrronium bromide, long-acting muscarinicantagonist, anticholinergic, bronchodilator

Amir Sharafkhaneh,1,2 Hashir Majid,3 Nicholas J Gross4 1Baylor College of Medicine, Department of Medicine, Houston, USA; 2Sleep Disorders Center, Michael E DeBakey VA Medical Center, Houston, USA; 3Aga Khan University, Karachi, Pakistan; 4Stritch School of Medicine Illinois, St Francis Hospital, Hartford, USA Abstract: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality. With the significant toll of the disease, more resources have been invested in developing new treatment modalities. Among these medications, inhalational anticholinergics are widely used for the management of stable COPD. The newer agents, with longer half-lives and better safety profiles, have emerged and helped to improve management of COPD patients. The available data from randomized clinical trials support use of these agents. Multiple randomized clinical trials show safety and efficacy of the newer long-acting inhaled anticholinergics, including tiotropium and aclidinium. A recent meta-analysis of tiotropium delivered with Respimat® raised some safety concerns. A large trial, comparing different doses and delivery methods of inhaled tiotropium, is ongoing to determine the effect on mortality. As clinical trials may not comprehensively represent the entire COPD population, caution should be exercised when these agents are used in higher-risk populations, like individuals with cardiac arrhythmias or urinary obstruction. In this publication, we review the safety of inhalational anticholinergics. Keywords: tiotropium, cardiovascular side effects, arrhythmia, stroke, aclidinium

BACKGROUND: Recently, there have been concerns about the tolerability of long-acting (2)-agonists, including possible adverse cardiovascular effects-a particular concern in patients with chronic obstructive pulmonary disease (COPD), who are at elevated risk for cardiovascular disease. OBJECTIVE: The aim of this study was to assess the cardiac safety profile of nebulized formoterol fumarate inhalation solution. METHODS: Cardiac safety was assessed as part of a 12-week, randomized, double-blind, double-dummy, placebo- and active-controlled trial that was conducted at 38 centers across the United States. Male and female patients aged >/=40 years with COPD and without other significant disease were enrolled. After a 4- to 14-day, single-blind placebo run-in period, patients with COPD were randomly assigned to receive formoterol fumarate inhalation solution 20 microg BID via nebulizer (FFIS group), formoterol fumarate 12 microg BID via dry powder inhaler (FA group), or placebo. Cardiac effects-measured by changes in heart rate (HR) and ventricular premature beats; incidence of proarrhythmic events; change in corrected QT (QTc) interval; and incidence of maximum mean change in QTc >/=60 ms-were assessed using 24-hour Holter monitoring at baseline and 12 weeks; 12-lead electrocardiography at screening and weeks 4, 8, and 12; and patient diary cards. RESULTS: A total of 351 patients with COPD were randomized (mean age, 62.8 years; 56.1% male; mean postbronchodilator forced expiratory volume in 1 second, 1.5 L). Holter monitoring found no clinically meaningful effects of FFIS or FA treatment on mean or maximum HR, ventricular premature beats, or inci dence of arrhythmic events compared with placebo. At week 12, mean (SD) changes from baseline in mean HR were -0.6 (10.9), +0.1 (11.6), and -1.4 (9.4) bpm in the FFIS, FA, and placebo groups, respectively. The incidence of mean maximum changes in QTc >/=60 ms at any time during the 12-week treatment period were 1.6%, 1.8%, and 1.8% with FFIS, FA, and placebo, respectively. Treatment-emergent cardiac adverse events (AEs) occurred in 4.1%, 3.5%, and 4.4% of patients in the FFIS, FA, and placebo groups; withdrawals due to possible cardiac AEs occurred in 1 patient per treatment group. No deaths or serious cardiac AEs occurred during the treatment period. CONCLUSION: In this COPD population, no clinically significant cardiac effects were found with twicedaily treatment with nebulized formoterol fumarate inhalation solution. [ABSTRACT FROM AUTHOR]

Even though chronic obstructive pulmonary disease is incurable, many treatments-both pharmacologic and nonpharmacologicare available to maximize lung function, alleviate symptoms, prevent and manage exacerbations, and improve quality of life. [ABSTRACT FROM AUTHOR]

Purpose: Idiopathic intracranial hypertension (IIH) leads to optic nerve head swelling and optic atrophy if left untreated. We wanted to assess an easy to perform volumetric algorithm to detect and quantify papilledema in comparison to retinal nerve fiber layer (RNFL) analysis using optical coherence tomography (OCT)., Methods: Participants with and without IIH underwent visual acuity testing at different contrast levels and static perimetry. Spectralis-OCT measurements comprised standard imaging of the peripapillary RNFL and macular ganglion cell layer (GCL). The optic nerve head volume (ONHV) was determined using the standard segmentation software and the 3.45 mm early treatment diabetic retinopathy study (ETDRS) grid, necessitating manual correction within Bruch membrane opening. Three neuro-ophthalmologists graded fundus images according to the Frisén scale. A mixed linear model (MLM) was used to determine differences between study groups. Sensitivity and specificity was evaluated using the area under the receiver-operating characteristic (ROC)., Results: Twenty-one patients with IIH had an increased ONHV of 6.46 ± 2.36 mm 3 as compared to 25 controls with 3.20 ± 0.25 mm 3 ( P < 0.001). The ONHV cutoff distinguishing IIH from controls was 3.97 mm 3 (i.e. no patient with IIH had an ONHV below and no healthy individual above this value). The area under the curve (AUC) for ONHV was 0.99 and for the RNFL at 3.5 mm 0.90. The Frisén scale grading correlated higher with the ONHV (r = 0.90) than with the RNFL thickness (r = 0.68). ONHV measurements were highly reproducible in both groups (coefficient of variation <0.01%)., Conclusions: OCT-based volumetry of the optic nerve head discriminates very accurately between individuals with and without IIH. It may serve as a useful adjunct to the rating with the subjective and ordinal Frisén scale., Translational Relevance: A simple OCT protocol run on the proprietary software of a commercial OCT device can reliably discriminate between normal optic nerve heads or pseudo-papilledema and true papilledema while being highly reproducible. Our normative data and OCT preset may be used in further clinical studies., Competing Interests: Disclosure: M. Dreesbach, None; L. Joachimsen, None; S. Küchlin, None; M. Reich, None; N.J. Gross, None; A.U. Brandt, None; F. Schuchardt, None; A. Harloff, None; D. Böhringer, None; W.A. Lagrèze, None, (Copyright 2020 The Authors.)

Introduction: Although the interest is growing in topical low-dose atropine to control myopia in schoolchildren worldwide, its use in children of European ancestry remains controversial and solid evidence is sparse. The Oxford Centre for Evidence Based Medicine (OCEBM) classifies the evidence for this therapy as level I for East Asian populations, but only level IV in non-Asian populations., Methods: Fifty-six children, aged a median of 11 years (range 6-17), were analysed after 12 months of topical treatment with 0.01% preservative-free atropine in both eyes at bedtime every day. Efficacy was assessed during treatment every 6 months. In a subset of 20 patients, treatment of the second eye was delayed by 1 day to enable a controlled safety assessment of side effects such as pupil dilation, hypoaccommodation, and near vision reduction., Results: Prior to treatment, the mean myopic progression was estimated as 1.05 D/year; after 12 months of treatment with 0.01% atropine, it was 0.40 D/year (p < 0.0001). The only consistently measurable side effect was the induction of 1 mm pupil dilatation, which was only noticeable in comparison to the non-treated eye during the safety investigation., Conclusions: Topical low-dose atropine appears to be safe and efficacious also in a cohort of European schoolchildren. These data should motivate researchers to conduct more randomised clinical trials.

Myopia is on the increase worldwide and will become a major challenge over the next decades in terms of secondary ophthalmologic complications. There are effective therapeutic options available to slow or prevent the progression of myopia. So far, it has not been investigated whether there are possible additive effects of these interventions. Further investigations - especially in Caucasian populations - are necessary to verify the study results available from Asia. There is limited data on how long further progression of myopia is preventable. A therapy appears reasonable as long as a progression of myopia is detectable.Consistent childhood amblyopia screening provides a cost-effective measure for the prevention of visual disturbances over the course of life. How this can be best integrated into the existing system of "U-investigations", must be clarified by the cost-bearers and professional associations. This discourse should be supported by close interdisciplinary exchange and further studies on the prevalence of different degrees of amblyopia. In addition, sensitive and specific or even multi-stage tests should be developed in order to implement an early detection that is cost-effective and saves resources., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: One of the most common side effects of mesiotemporal lobe resection in patients with medically intractable epilepsy are visual field defects (VFD). While peripheral defects usually remain unnoticed by patients, extended VFD influence daily life activities and can, in particular, affect driving regulations. This study had been designed to evaluate frequency and extent of VFD following different surgical approaches to the mesiotemporal area with respect to the ability to drive., Materials and Methods: This study comprises a consecutive series of 366 patients operated at the Epilepsy Center in Freiburg for intractable mesiotemporal lobe epilepsy from 1998 to 2016. The following procedures were performed: standard anterior temporal lobectomy (ATL: n=134; 37%), anterior temporal or keyhole resection (KH: n=53; 15%), and selective amygdalohippocampectomy via the transsylvian (tsAHE: n=145; 40%) and the subtemporal (ssAHE: n=34; 9%) approach. Frequency and extent of postoperative VFD were evaluated in relation to different surgical procedures. According to the German driving guidelines, postoperative VFD were classified as driving-relevant VFD with the involvement of absolute, homonymous central scotoma within 20° and driving-irrelevant VFD with either none or exclusively minor VFD sparing the center., Results: Postoperative visual field examinations were available in 276 of 366 cases. Postoperative VFD were observed in 202 of 276 patients (73%) and were found to be driving-relevant in 133 of 276 patients (48%), whereas 69 patients (25%) showed VFD irrelevant for driving. Visual field defects were significantly less likely following ssAHE compared with other temporal resections, and if present, they were less frequently driving-relevant (p<0.05), irrespective of the side of surgery., Conclusion: Subtemporal sAHE (ssAHE) caused significantly less frequently and less severely driving-relevant VFD compared with all other approaches to the temporal lobe, irrespective of the side of surgery., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Purpose: To assess the accuracy of ocular B-mode sonography and of standard head computed tomography (CT) as screening tools for intraocular hemorrhages related to subarachnoid hemorrhage (SAH)., Methods: 46 patients with spontaneous SAH were examined using ocular B-mode sonography and underwent funduscopy as gold standard for detection of ocular hemorrhages (OH). Additionally, all head CT scans done during the hospital stay of the study population were rated by a neuroradiologist for the presence of OH., Results: Funduscopy revealed vitreous and/or preretinal hemorrhages in ten eyes and retinal hemorrhages in nine eyes. In comparison with funduscopy, ocular sonography showed a sensitivity and specificity for the detection of vitreous and/or preretinal hemorrhages of 100%, while identification of retinal hemorrhages was less reliable with a sensitivity/specificity of 44%/100%. Standard head CT showed a lower sensitivity/specificity of 60%/96% for vitreous and/or preretinal hemorrhages, and 32%/95% for the diagnosis of any ocular bleeding., Conclusion: Ocular sonography identifies SAH-related preretinal and vitreous hemorrhages with high accuracy and is superior to standard head CT. It may be considered as new and useful bedside diagnostic tool for routine clinical care of patients with SAH., (Copyright © 2015 by the American Society of Neuroimaging.)

Aim: Although contrast vision is not routinely tested, it is important: for instance, it predicts traffic incidents better than visual acuity. Mesopic contrast sensitivity (CS) testing approximates low-lighting conditions but entails dark adaptation, which can disrupt clinical routine. In receptor-specific diseases, a dissociation of photopic and mesopic sensitivity would be expected, but can photopic CS act as a surrogate measure for mesopic CS, at least for screening purposes?, Methods: Photopic and mesopic contrast sensitivities were studied in three groups: 47 normal subjects, 23 subjects with glaucoma, and three subjects with cataract. Twenty-eight of the normal subjects were additionally tested with artificial blur. Photopic contrast sensitivity was assessed with both the Freiburg Acuity and Contrast Test (FrACT) and the Mars Letter Contrast Sensitivity Charts. Mesopic contrast sensitivity, without and with glare, was measured with the Mesoptometer IIb. Coefficients of repeatability and limits of agreement were calculated for all tests., Results: Test-retest limits of agreement were ± 0.17 logCS for Mars, ± 0.21 logCS for FrACT, and ±0.20 logCS / ± 0.14 logCS for Mesoptometer IIb without and with glare, respectively. In terms of inter-test comparison, Mars and FrACT largely agreed, except for ceiling effects in the Mars test. While mesopic and photopic contrast sensitivities correlate significantly (r  = 0.51, p < 0.01), only 27 % of the variance is in common. In particular, subjects with high photopic results may be nearly as likely to have low as well as high mesopic results., Conclusions: The photopic contrast sensitivity tests assessed here cannot serve as surrogate measures for current mesopic contrast sensitivity tests. Low photopic CS predicts low mesopic CS, but with normal photopic CS, mesopic CS can be normal or pathologic.

Background: This study compared the postoperative results and patient satisfaction between penetrating keratoplasty (PK) and Descemet stripping automated endothelial keratoplasty (DSAEK) in patients who underwent PK in one eye and DSAEK in the other eye., Methods: A total of 15 patients were identified from the corneal database register and the medical charts were analyzed for best corrected visual acuity (BCVA), keratometric astigmatism, endothelial cell density and postoperative complications. Patient satisfaction was evaluated by a standardized interview., Results: Median follow-up time for PK was 55 months and 18 months for DSAEK (p < 0.01). Median BCVA in PK was 0.8 and 0.5 in DSAEK (p = 0.01) at the end of follow-up. Median keratometric astigmatism was 3.1 diopters after PK and 1.9 diopters after DSAEK (p = 0.2). Median endothelial cell density was 831 cells/mm(2) after PK and 860 cells/mm(2) after DSAEK (p = 0.63). For the interventions 57 % of the patients preferred PK, 36 % preferred DSAEK and 7 % were undecided. Patients assigned the better performing eye to the PK side in 64 % and in 29 % to the DSAEK side and 7 % perceived equal visual performance in both eyes., Conclusion: The results leave doubt about the superiority of DSAEK compared to PK; however, exceptionally good refractive results of the 15 PK eyes analyzed and significantly longer follow-up times after PK could be the reason for the unexpectedly high patient preference for PK.

Background: Surgical correction of intermediate squint angles may be performed on one muscle alone or as a combined unilateral recess-resect procedure. No larger case series has yet systematically measured the amount of induced incomitance that could potentially lead to visual disturbances., Methods: 31 patients with strabismus and binocular vision (phoria or intermittent strabismus) were operated on one extraocular eye muscle; 30 patients underwent a unilateral recess-resect procedure. Preoperatively and three months postoperatively, we measured the latent angle of squint on a tangent screen over the horizontal 60° in 10° increments and then calculated the amount of induced incomitance., Results: After one muscle surgery, the induced incomitance was 1.7° over a 20° gaze range, 3.2° over a 40° gaze range and 3.8° over a 60° gaze range. For recess-resect procedures, the induced incomitance was 1.4°, 2.6° and 3.4°, respectively. A significant correlation between the surgical dose and the induced incomitance was only seen in one muscle surgery for the 40° and 60° gaze range, but not for the 20° gaze range. A subgroup analysis of patients with an identical surgical dose in one and two muscle procedures (6-8 mm) found greater induced incomitance in one muscle procedures, but only for the 40° and 60° gaze range (p = 0.02). Double vision in any gaze direction was reported by 16 % of patients after one muscle surgery and 10 % of patients after unilateral recess-resect surgery (p > 0.05)., Conclusion: One muscle surgery is a viable option in small and intermediate angles of squint. The induced incomitance is rather small and does not lead to significant visual disturbances in the central gaze range., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: A causal relationship between glaucoma and obstructive sleep apnea has been postulated in several clinical studies but also refuted by others. The aim of this study was to determine the prevalence of glaucoma in a cohort of patients with well-established obstructive sleep apnea in comparison to the published data on this topic., Methods: A total of 100 consecutive patients (male:female  80:20, mean age 59 ± 11 years SD) with polysomnographically established obstructive sleep apnea underwent an ophthalmological examination including tonometry, static perimetry and dilated fundus photography. Visual fields and fundus photographs of the patients were classified as glaucomatous or non-glaucomatous by two independent examiners., Results: The prevalence of glaucoma in the study patients was 2 % which corresponded to the published prevalence of glaucoma in the normal population. Intraocular pressure did not correlate with the respiratory index, body mass index or sex., Conclusion: The data from this study shed doubt on a causal relationship between obstructive sleep apnea and glaucoma.

Background: Chronic obstructive pulmonary disease (COPD) affects an estimated 14% of adults in the United States between the ages of 40 and 79 years. This progressive disease is characterized by persistent airflow limitation. The management of patients with COPD is focused on reducing risk factors, relieving symptoms, and preventing exacerbations., Objective: To examine the peer-reviewed literature on the impact of maintenance therapy on the direct treatment costs of patients with COPD in the United States., Methods: PubMed was searched for articles written in English that were published between 2000 and 2013, using the search terms "COPD," "economics," "exacerbation," "maintenance," and related terms. Articles reporting the results of longitudinal studies of the costs associated with the management of patients with COPD, the costs associated with hospitalizations for acute exacerbations of COPD, and randomized clinical trials evaluating the effects of maintenance therapy on the incidence of COPD exacerbations were included in this review., Results: The search identified a total of 277 articles, and 11 of these articles were deemed appropriate for inclusion in this review. The direct healthcare costs for patients with COPD increased by 38% between 1987 and 2007, and continued to increase by approximately 5% annually between 2006 and 2009. The costs associated with hospital admissions for patients with COPD accounted for the largest absolute increase ($2289 per admission in constant 2007 US dollars). Recent estimates suggest that the aggregate costs associated with the treatment of acute exacerbations are between $3.2 billion and $3.8 billion, and that annual healthcare costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations. The results of 2 large clinical trials of maintenance therapy, including a long-acting cholinergic antagonist or a long-acting beta-2 agonist, showed a 16% to 17% reduction in the incidence of exacerbations compared with placebo. Nevertheless, maintenance therapy remains underutilized, with only 30% to 35% of patients with COPD in private and public health insurance plans receiving prescriptions for maintenance therapy., Conclusions: The treatment of acute exacerbations of COPD remains the major driver of increasing healthcare costs associated with this condition. The appropriate use of maintenance therapy has been shown to reduce the incidence of exacerbations and has the potential to reduce overall costs associated with the management of patients with COPD.

The biologic nature of COPD inflammation is not well understood and agents that inhibit inflammation in COPD are a major unmet need. However, a variety of agents that have the potential to be inhibitors of COPD inflammation are in various stages of development. Agents that have been approved for a non-COPD indication but that have potential for inhibiting COPD inflammation include the statins, some phosphodiesterase inhibitors, some long-acting β agonists, tiotropium bromide, the peroxisome proliferator-activated receptor-γ agonist rosiglitazone, and various monoclonal antibodies. New molecular entities that are being developed specifically as antiinflammatory agents for COPD include a variety of chemokine receptor antagonists, inhibitors of matrix metalloproteinases, inhibitors of p38 mitogen-activated protein kinases, and stem cells. Some other novel agents that are in preclinical or early clinical stages are mentioned.

Background: The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD)., Methods: In two double-blind, 52-week studies, ACCLAIM/COPD I (n=843) and II (n=804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of ≤70% and FEV1<80% of the predicted value. The primary endpoint was trough FEV1 at 12 and 28 weeks. Secondary endpoints were health status measured by St George's Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation., Results: At 12 and 28 weeks, aclidinium improved trough FEV1 versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p<0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p<0.001). More patients had a SGRQ improvement≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p=0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p=0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p=0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p=0.9). Adverse events were minor in both studies., Conclusion: Aclidinium is effective and well tolerated in patients with moderate to severe COPD., Trial Registration: ClinicalTrials.gov: NCT00363896 (ACCLAIM/COPD I) and NCT00358436 (ACCLAIM/COPD II).

A nebulized formulation of formoterol, Perforomist, 20 microg/2 ml, has been available since 2007 for the maintenance treatment of chronic obstructive pulmonary disease (COPD). We review the safety and efficacy data obtained during its development. In a dose-finding study, formoterol inhalation solution (FFIS) was similar to the formoterol originator, Foradil 12 microg DPI (FA) in patients with COPD. In a 12-week efficacy study, FFIS manifested a rapid onset of action and FEV(1) peak, AUC(0-12), and trough levels similar to FA. No loss of efficacy, tachyphylaxis, was observed over 12 weeks of regular administration. In placebo-controlled studies in COPD patients receiving maintenance tiotropium, the addition of FFIS significantly augmented bronchodilation over the 6-week treatment duration, signifying that nebulized formoterol can further improve lung function in patients who are receiving tiotropium without an observed increase in adverse reactions. The safety profile of FFIS during 12-week and 1-year studies revealed adverse events that were similar to those of placebo and FA. Cardiac rhythm studies, including frequent ECGs and Holter monitoring, did not indicate any increase in rate or rhythm disturbances greater than placebo or FA. We conclude that maintenance use of Perforomist is appropriate for patients with COPD who require or prefer a nebulizer for management of their disease.

Recent advances in chronic obstructive pulmonary disease (COPD) treatment offer symptom relief, but disease modification remains an unmet goal of pharmacotherapy. Reducing the frequency and severity of COPD exacerbations may help slow disease progression and reduce the morbidity, mortality, and costs associated with these major events. Other desirable characteristics for a COPD treatment include a once-daily dosing schedule, an oral formulation, and a low frequency of systemic side effects. Phosphodiesterase 4 inhibitors have been in clinical development for some years and roflumilast is currently the most advanced of these agents. In this review, the preclinical evidence, clinical safety, and efficacy of roflumilast available in published reports are considered. The data reviewed here suggest that the clinical efficacy of roflumilast occurs through a mechanism unrelated to bronchodilation and may be due to the suppression of lung inflammation. Lung function improved with roflumilast treatment and in some studies, the reduction in exacerbations was substantial and statistically significant. Notably, this effect appeared to be greatest in the subgroup of patients with more severe disease and more severe exacerbations. The evaluation of roflumilast safety largely centers on gastrointestinal adverse events, with diarrhea, nausea, and weight loss occurring more frequently with the drug than placebo. If approved for general use, we expect roflumilast to find its role initially as a substitute for inhaled corticosteroids in the maintenance treatment of severe and very severe disease, particularly in patients who have frequent acute exacerbations, and perhaps as a supplementary drug when symptoms are not adequately controlled by current conventional COPD therapy.

Tiotropium is commonly used in the treatment of chronic obstructive pulmonary disease. Although largely considered to be a long-acting bronchodilator, its demonstrated efficacy in reducing the frequency of exacerbations and preliminary evidence from early studies indicating that it might slow the rate of decline in lung function suggested mechanisms of action in addition to simple bronchodilation. This hypothesis was examined in the recently published UPLIFT study and, although spirometric and other clinical benefits of tiotropium treatment extended to four years, the rate of decline in lung function did not appear to be reduced by the addition of tiotropium in this study. This article summarizes data from a variety of investigations that provide insights into possible mechanisms to account for the effects of tiotropium. The report summarizes the discussion on basic and clinical research in this field.

Chronic obstructive pulmonary disease is a prevalent condition associated with a high societal burden. Despite a decrease in the prevalence of smoking in the United States, the rates of morbidity and mortality associated with chronic obstructive pulmonary disease are expected to continue to increase. Appropriate treatment can have an important impact on many facets of the disease. This article reviews evidence gathered in a PubMed search of papers published from January 1, 2004, to December 31, 2007. The search terms used were chronic obstructive pulmonary disease, epidemiology, practice guidelines, clinical trial, and meta-analysis. Selection of pharmacological therapy is based on severity of disease and differences among the effects of drugs on various end points, including the criterion standard, forced expiratory volume in the first second of expiration. Other important variables, which are closely related to patients' perception of their condition, include reduction in acute exacerbations, improved quality of life, improved exercise performance, and reduced hyperinflation. When maintenance therapy is indicated, clinical evidence suggests initiating treatment with a long-acting agent, either a once-daily anticholinergic or a twice-daily beta2-agonist. If combination therapy is indicated, data support using long-acting drugs from different classes that provide complementary modes of action (beta2-agonist, anticholinergic, inhaled corticosteroid). In this setting, inhaled corticosteroids may further reduce exacerbations when given with a beta2-agonist, an anticholinergic, or both.

To determine a dose of nebulized formoterol fumarate inhalation solution (FFIS) comparable to that of the marketed formoterol fumarate dry powder inhaler (FA, 12microg), two crossover studies were conducted in subjects with COPD. Study 1 was a single-dose, double-blind, double-dummy dose-ranging study in which 47 subjects were randomly assigned to treatment sequences that evaluated the bronchodilatory effects of FFIS 2.5, 5, 10, 20, and 40microg, FA, and placebo over 12h. Mean FEV(1) AUC(0-12) following FFIS treatment ranged from 1.3 to 3.0l/h in a dose-related manner, with equivalent values (2.3l/h) for FFIS 20microg and FA. Results for other spirometric measures, including peak and trough FEV(1) and absolute change in FEV(1) by timepoint, confirmed the comparability of FFIS 20microg and FA. Study results with the nebulized formulation supported the rapid time to onset of bronchodilation with FFIS 20microg (3.9 and 2.2min imputed for 15% and 12%/200ml response, respectively). Study 2, a single-dose, open-label crossover study, was conducted to establish the pharmacokinetic (PK) profile of nebulized formoterol and confirm comparability to FA. Thirteen subjects were randomly assigned to treatment sequences with FFIS 10, 20, and 244microg and FA with a 5-14-day washout period between each treatment. Formoterol levels were assessed from blood and urine collected pre-dose and over a 24-36-h period after dosing. Pharmacodynamic (PD) measures included clinical laboratory and ECG measures pre-dose and over a 24-h period post-dose. FFIS 244mug was rapidly absorbed with a T(max) of 12min and t(1/2) of 6.1h. Data from other doses were sporadic due to assay sensitivity. The mean amount excreted (Ae) in urine suggested linear kinetics and confirmed the comparability of FFIS 20microg and FA. Mean serum potassium decreased and mean serum glucose increased transiently in a dose-dependent manner following treatment. No clinically significant ECG changes were observed; mean heart rate increased after treatment with FFIS 244mug by up to 6bpm. Findings from dose-ranging and PK/PD studies confirmed that a 20microg dose of FFIS was comparable to formoterol fumarate delivered by dry powder inhalation (12microg) and established the dose proportionality and linear kinetics of formoterol fumarate delivered by nebulization.

Anti-VEGF treatment has become accepted first-line treatment for choroidal neovascularisation (CNV) in age-related macular degeneration. However, VEGF-inhibition does not always lead to sustained CNV-reduction. In this study, the effect of rapamycin was superior to VEGF-inhibition in a co-culture assay of endothelial cells (ECs) and retinal pigment epithelium (RPE). Rapamycin reduced EC sprouting in groups that did not respond to anti-VEGF treatment. Rapamycin did not induce EC apoptosis, but reduced both VEGF-production in RPE and the responsiveness of ECs to stimulation. Rapamycin might therefore be a therapeutic option for CNV patients that do not respond sufficiently to the established anti-VEGF treatments.

Nebulized solutions of long-acting bronchodilators provide an alternative to DPI and MDI delivery, particularly for COPD patients unable to use hand-held devices easily or correctly. The long-acting beta2-agonist, formoterol fumarate, is differentiated by its onset of significant bronchodilation within 5 min of administration. In a randomized, double-blind, double-dummy trial, COPD subjects (n=351, mean forced expiratory volume FEV1=1.3 L, 44% predicted) received nebulized formoterol fumarate (Perforomist inhalation solution; FFIS 20 microg) or DPI (Foradil Aerolizer; FA 12 microg), or placebo twice daily for 12 weeks. Efficacy was assessed with 12-h pulmonary function tests, and quality of life was assessed before and after treatment with the St. George's Respiratory Questionnaire (SGRQ). At the 12-week endpoint, FFIS significantly increased FEV1 AUC0-12h relative to placebo (p<0.0001). No evidence of tachyphylaxis was observed as indicated by maintained FEV1 AUC and reduced rescue albuterol use throughout treatment. FFIS also significantly increased peak FEV1, trough FEV1, and standardized FVC AUC0-12h compared with placebo. SGRQ assessment at Week 12 demonstrated significant and clinically meaningful improvements in total score (FFIS vs placebo, -4.9, p=0.0067), symptom, and impact scores. No significant differences in efficacy were observed between the two active treatments. Drug related AEs in the FFIS arm with a frequency > or = 1% and exceeding placebo were dry mouth, nausea, and insomnia. Nebulized FFIS provided significant improvement in respiratory status and quality of life in subjects with COPD relative to placebo and was well tolerated. The efficacy and safety profile of FFIS was comparable to FA DPI.

Anticholinergic agents have important uses as bronchodilators for the treatment of obstructive airway diseases, both asthma and, more particularly, chronic obstructive pulmonary disease (COPD). Those in approved clinical use are synthetic quaternary ammonium congeners of atropine, and include ipratropium bromide, oxitropium bromide, and tiotropium bromide, each of which is very poorly absorbed when given by inhalation. Ipratropium and oxitropium have relatively short durations of action (4-8 h). They have been widely used for many years, either alone or in combination with short-acting beta-adrenergic agents such as albuterol and fenoterol, for both maintenance treatment of stable disease and for acute exacerbations of airway obstruction. Tiotropium, which was introduced in the early 2000s, has a duration of action of at least 1-2 days making it suitable for once-daily maintenance treatment of COPD. All of the above agents have a wide therapeutic margin and are safe and well tolerated by patients.

The severity of chronic obstructive pulmonary disease (COPD) and patients' response to therapy are difficult to assess. The traditional measure, spirometry, correlates poorly with important clinical features of the disease, such as survival and quality of life (QOL). Moreover, COPD has recently been recognized as a systemic disease, and its systemic manifestations, such as weight loss and muscle weakness, are only poorly related to lung function. Therefore, although lung function remains an important outcome, other outcomes must be included in any overall assessment of disease severity or response to interventions. Examples include refinements of spirometry, such as measurement of FEV6 and inspiratory capacity; functional outcomes, such as dyspnea indexes and exercise tests; and global-clinical outcomes, such as QOL questionnaires and assessment of frequency and severity of acute exacerbations. For scoring disease severity, making a prognosis, or determining the outcome of novel interventions, composite measures need to be developed that take into account as many aspects of COPD as practicable.

Tiotropium bromide is a novel, inhaled, once-daily anticholinergic bronchodilator that has recently been approved in the United States for use in patients with COPD. Its unique feature is the persistence of bronchodilation for > 24 h due to prolonged M(3) muscarinic receptor blockade. Tiotropium provides significant improvement in spirometry and lung volumes. Clinically relevant outcomes such as the relief of dyspnea, improvement in the quality of life (health status), and reductions in the frequency and severity of acute exacerbations have been consistently obtained with tiotropium in clinical trials. In head-to-head trials, tiotropium administered once daily resulted in bronchodilation (peak, trough, and area under the curve) that was statistically superior to ipratropium administered four times daily and salmeterol administered twice daily. Clinical outcomes (dyspnea, quality of life, exacerbation frequency) were numerically but not always statistically better with tiotropium than salmeterol. Long-term studies of the combination of tiotropium with adrenergic agents, methylxanthines, or inhaled corticosteroids have not been reported in full. Several 1-year studies demonstrate that the only significant side effect of tiotropium was dryness of the mouth, which occurred in approximately 10 to 16% of patients; it is well tolerated by patients and safe.