https://www.lumc.nl/sub/1070/att/91028021319455/100317115032452.pdf

Roflumilast--an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial.

The preclinical pharmacology of roflumilast--a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease.

Phosphodiesterase inhibitors in airways disease

Chief Editors: John M. Weiler, MD, MBA, President, CompleWare Corporation, Professor Emeritus, University of Iowa, Iowa City, Iowa; Sandra D. Anderson, PhD, DSc, Clinical Professor, Sydney Medical School, Royal Prince Alfred Hospital, Department of Respiratory and Sleep Medicine, Camperdown NSW 2050, Australia; Christopher Randolph, MD, Clinical Professor of Pediatrics, Yale Affiliated Programs, Waterbury Hospital, Center for Allergy, Asthma and Immunology, Waterbury, Connecticut

/pdf/pathogenesis-prevalence-diagnosis-and-management-of-exercise-15cs5qxwl5.pdf

Pathogenesis, prevalence, diagnosis, and management of exercise-induced bronchoconstriction: a practice parameter

The first practice parameter on exercise-induced bronchoconstriction (EIB) was published in 2010. This updated practice parameter was prepared 5 years later. In the ensuing years, there has been increased understanding of the pathogenesis of EIB and improved diagnosis of this disorder by using objective testing. At the time of this publication, observations included the following: dry powder mannitol for inhalation as a bronchial provocation test is FDA approved however not currently available in the United States; if baseline pulmonary function test results are normal to near normal (before and after bronchodilator) in a person with suspected EIB, then further testing should be performed by using standardized exercise challenge or eucapnic voluntary hyperpnea (EVH); and the efficacy of nonpharmaceutical interventions (omega-3 fatty acids) has been challenged. The workgroup preparing this practice parameter updated contemporary practice guidelines based on a current systematic literature review. The group obtained supplementary literature and consensus expert opinions when the published literature was insufficient. A search of the medical literature on PubMed was conducted, and search terms included pathogenesis, diagnosis, differential diagnosis, and therapy (both pharmaceutical and nonpharmaceutical) of exercise-induced bronchoconstriction or exercise-induced asthma (which is no longer a preferred term); asthma; and exercise and asthma. References assessed as relevant to the topic were evaluated to search for additional relevant references. Published clinical studies were appraised by category of evidence and used to document the strength of the recommendation. The parameter was then evaluated by Joint Task Force reviewers and then by reviewers assigned by the parent organizations, as well as the general membership. Based on this process, the parameter can be characterized as an evidence- and consensus-based document.

Exercise-induced bronchoconstriction update-2016.

Roflumilast is a new phosphodiesterase 4 (PDE4) inhibitor developed by Byk Gulden Pharmaceuticals for the treatment of chronic obstructive pulmonary disease and asthma. A placebo-controlled, randomized, double-blind, two-period crossover study was performed to investigate the safety and efficacy of roflumilast in 16 patients with exercise-induced asthma. The patients received placebo or roflumilast (500 microg/day) for 28 days, each according to the randomly determined treatment sequences roflumilast/placebo and placebo/roflumilast. In both study periods, exercise challenge was performed 1 hour after dosing on days 1, 14, and 28. FEV1 was measured before exercise challenge, immediately after the end of exercise challenge, and then at 1, 3, 5, 7, 9, and 12 minutes after the end of challenge. Blood samples for the determination of lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF-alpha) in whole blood ex vivo as a surrogate marker for the inhibition of inflammatory cell activation were taken predose on days 1 and 28. Serial safety measurements were performed during both study periods. Analysis of variance for the crossover design showed a significant superiority of roflumilast over placebo on day 28. The mean percentage fall of FEV1 after exercise was reduced by 41% as compared to placebo (p = 0.021). An improvement of lung function during roflumilast treatment was also observed on days 1 and 14. The median TNF-alpha level decreased by 21% (p = 0.009) during roflumilast treatment but remained essentially constant under placebo. It is concluded that roflumilast is effective in the treatment of exercise-induced asthma. This result was accompanied by a significant reduction of TNF-alpha levels ex vivo. Treatment with roflumilast was safe and well tolerated.

The New Phosphodiesterase 4 Inhibitor Roflumilast Is Efficacious in Exercise‐Induced Asthma and Leads to Suppression of LPS‐Stimulated TNF‐α Ex Vivo

The pharmacokinetics and safety of the ketolide telithromycin were evaluated in two separate studies after single and repeat oral dosing in patients with varying degrees of renal impairment and in subjects with normal renal function. The single-dose study was an open-label, nonrandomized, parallel-group design in which all 40 patients received a single oral dose of telithromycin 800 mg. The repeat-dose study was an open-label study with a randomized, balanced, incomplete three-block treatment crossover design. In this study, each of the 36 patients received two of three telithromycin regimens (400, 600, or 800 mg once daily for 5 days), with a washout period of >/= 7 days between treatments. Telithromycin was well tolerated. Adverse events were generally mild in severity, and no serious drug-related adverse events were reported. Plasma exposure to telithromycin (C(max), AUC) showed a tendency to increase with increasing severity of renal impairment in both studies. In patients with severe renal impairment (CL(CR) /= 30 mL/min). In patients with severe renal impairment (CL(CR) < 30 mL/min), dosage adjustment could be considered.

Pharmacokinetics and Safety of the Ketolide Telithromycin in Patients with Renal Impairment

Zolmitriptan, an oral 5HT1D agonist for the acute treatment of migraine, is cleared from the systemic circulation mainly by hepatic metabolism. Consequently, changes in hepatic function may result in changes in the pharmacokinetics of zolmitriptan. This open, parallel-group study was conducted to compare the pharmacokinetics and tolerability of a single 10-mg dose of zolmitriptan in healthy subjects and patients with hepatic impairment. A total of 37 participants entered and completed the study, including 10 healthy volunteers, 11 patients with moderate hepatic impairment, 10 patients with severe hepatic impairment without ascites, and 6 patients with severe hepatic impairment with ascites. The metabolism of zolmitriptan was reduced in patients with severe hepatic impairment compared with healthy subjects, resulting in higher peak plasma concentrations (47%), increased exposure (226%), and prolonged half-life (157%). The changes were similar in the presence and absence of ascites. Smaller changes were observed in patients with moderate hepatic impairment. Plasma concentrations of the three major metabolites of zolmitriptan were reduced in the patients with hepatic impairment. Patients with moderate hepatic impairment require no dosage adjustment, but the recommended daily intake of zolmitriptan may need to be reduced in patients with severe hepatic impairment.

Effect of Hepatic Impairment on the Pharmacokinetics of Zolmitriptan

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Papers

The New Phosphodiesterase 4 Inhibitor Roflumilast Is Efficacious in Exercise‐Induced Asthma and Leads to Suppression of LPS‐Stimulated TNF‐α Ex Vivo

Pharmacokinetics and Safety of the Ketolide Telithromycin in Patients with Renal Impairment

Effect of Hepatic Impairment on the Pharmacokinetics of Zolmitriptan