Block D - therapies for COPD

Question 1

what is roflumilast ?what is roflumilast ?

Answer 1

type 4 phosphodiesterase (PDE) inhibitor >

Question 2

mwchanism od mechanism of action ?

Answer 2

The active component is believed to be Roflumilast-oxide. It inhibits PDE4 in which there are 4 different isoforms, with little inhibitory activity against other PDE isoforms (there are 11 members of the PDE family expressed in different parts of the body).

PDE4 catalyses the conversion of cyclic AMP into adenosine monophosphate by hydrolysing the ester bond between phosphate and the ribose group. By inhibiting PDE4 the cAMP accumulates in the cell and activates PKA which phosphorylates proteins and reduces inflammation involved in neutrophils and has anti-COPD effects. It also has an anti-fibrotic effect.

Anti inflammatory

Anti fibrotic

Symptomatic relief by inducing bronchodilation

Question 3

what is roflumilast metabolised by ?

Answer 3

Roflumilast is metabolised in the liver by cytochrome P450 , metabolism of the drug does not affect the ability to inhibit the PD4 family.

Question 4

is rolfmuilast selective is roflumilast selective and what does this mean ?

Answer 4

As roflumilast is selective for PD4 this reduces the side effects , but as it is not specific within the PD4 family some side effects may occur here.

Question 5

Cilomast ?

Answer 5

Cilomilast significantly improved lung function and reduced exacerbation rates in COPD (Giembycz, 2006).Cilomilast is associated with gastrointestinal disturbances,such as emesis and nausea (Boswell-Smith and Spina, 2007).

Question 6

olgemast ?

Answer 6

Oglemilast inhibited pulmonary cell infiltration, including eosinophilia and neutrophilia (Vakkalanka et al., 2004; Giembycz, 2008).

Question 7

Titomilast ?

Answer 7

Tetomilast is a once-daily oral PDE4 inhibitor that is currently in development for COPD and ulcerative colitis (O’Mahony, 2005; Schreiber et al., 2007);

Question 8

ONO-6126 ?

Answer 8

ONO-6126 has been tested in healthy subjects (Furuie et al., 2003; Giembycz, 2008) and is believed to be in Phase II development, while ELB353 has exhibited a good efficacy profile in animal models of pulmonary neutrophilia (Pages et al., 2009), and a further Phase I trial is underway to study its safety and pharmacokinetics in healthy subjects.

Question 9

biological effects of rolfimlast on clearance of sputum in vitro ?

Answer 9

In vitro, inhibition of PDE4 results in a wide range of effects, including increased

apoptosis (which may result in the clearance of sputum)

Question 10

inflammatory mediators in vitro ?

Answer 10

decreased release of inflammatory mediators in neutrophils (a reduction in influx resulting in a reduction of neutrophils in the airways)

Question 11

decreased expression of cell surface markers in vitro ?

Answer 11

Decreased expression of cell surface markers in many cell types (e.g. adhesion molecules in T-cells

Question 12

decreased release of cytokines in vitro ?

Answer 12

decreased release of cytokines in many cell types (such as tumour necrosis factor alpha, interleukin-1b and interleukin-10 in macrophages).

Question 13

in vivo inhibition of PDE4 ?

Answer 13

In vivo, inhibition of PDE4 leads to a broad spectrum of effects, such as the

inhibition of cell trafficking, and cytokine and chemokine release from inflammatory cells such as neutrophils, eosinophils, macrophages and T-cells

Question 14

animal studies ?

Answer 14

Animal studies with roflumilast demonstrated that it reduced the accumulation of

neutrophils in bronchoalveolar lavage fluid. Roflumilast was able to prevent bleomycin-induced lung infiltration of neutrophils and macrophages in mice.

Question 15

roflumilast for inflammatory activity ?

Answer 15

PDE4 inhibitors block the pro-inflammatory activity of a number of different cell types involved in cOPD. The most important are Macrophages (express PDE4B) and neutrophils.

Question 16

what does cytokchrome P450 (CYP) 3A4 and 1A2 do ?

Answer 16

Roflumilast is rapidly converted by cytochrome P450 (CYP) 3A4 and 1A2 to its active metabolite roflumilast N-oxide.Estimated to contribute ~90% of the total PDE4 inhibitory (tPDE4i) activity of roflumilast Roflumilast N-oxide is primarily cleared by CYP3A4, with some contribution from CYP2C19 and extrahepatic CYP1A1.

Question 17

plasma level after oral administration ?

Answer 17

Roflumilast is rapidly and almost completely absorbed after oral administration, with maximum plasma concentrations (Cmax) reached within ~1 h in healthy volunteers. Absolute bioavailability is ~80% when administered as an immediate-release tablet.

Question 18

theraputic dose?

Answer 18

The therapeutic dose is 500 mg, taken once daily. On repeated oral dosing with roflumilast 500 mg once daily in healthy subjects, the free drug concentration of roflumilast N-oxide in plasma over 24 h was estimated to be about 1–2 nM, following the measurement of plasma protein binding of roflumilast N-oxide of approximately 97%.

Question 19

dose levels when interaction with drugs occur such as erthromycin ?

Answer 19

Drug interaction studies have shown that no dose adjustment of roflumilast 500 mg was required when co-administered with erythromycin, ketoconazole, midazolam, digoxin and Maalox®, an antacid containing magnesium hydroxide and aluminium hydroxide

Question 20

weight loss and roflumilast ?

Answer 20

Weight loss has been reported in subjects treated with roflumilast and is also seen with the non-selective PDE inhibitor theophylline.

Investigation of the mechanisms of lipolysis in human adipocytes found that PDE3B and PDE4 regulate cAMP pools that affect the activation/phosphorylation state of AMP activated protein kinase, thereby influencing lipolysis. When AMP levels are low this occurs to increase energy levels.

Question 21

rolipram ?

Answer 21

Rolipram, a selective PDE4 inhibitor has been shown to increase plasma glucagon-like peptide-1 (GLP-1) concentrations in rats, suggesting PDE4D may play an important role in regulating GLP-1. GLP-1 can also influence lipolysis.

Question 22

what did a 12 week placebo controlled study of roflumilast reveal of plasma glucose levels ?

Answer 22

In a 12-week, placebo-controlled study of roflumilast 500 mg once daily in 205 newly diagnosed, treatment-naïve patients with DM2 (study M2-401), plasma glucose levels decreased significantly more in the roflumilast group than in the placebo group.

Question 23

in what types of COPD is roflumilast effective ?

Answer 23

Roflumilast has efficacy in chronic bronchitis + emphysema patients with and without steroid treatment.

Question 24

roflumilast and SAMA and LABA ?

Answer 24

Roflumilast reduces the exacerbation of COPD in combination with short acting muscarinic receptor antagonists (SAMA) and long acting beta adrenoceptor agonists (LABA)

Question 25

roflumilast and FEV1 ?

Answer 25

Roflumilast increases the bronchodilator FEV1 in COPD patients in combination with short acting muscarinic receptor antagonists and long acting beta adrenoceptor agonists.

Question 26

side effects of roflumilast ?

Answer 26

significant differences in GI tract disturbance (10%), weight loss

Question 27

side effects of isoforms PDE4D ?

Answer 27

Studies in knockout mice have suggested that PDE4D is the main isoform associated with emesis ( vomitting)