Lecture 12 - emerging therapies Flashcards
what is involved in drug discovery process?
target selection, lead discovery, medicinal chemistry, in vitro studies, in vivo studies, clinical trials and therapeutics
why is Raflumilast developed for copd?
raising cyclic AMP in cells of the airways is anti-inflammatory effect - it inhibits inflammation
raising cyclic amp activates PKA, which inhibits the expression of pro-inflammatory cytokine events, by inhibiting NF-Kb. PKA activates transcription factor CREB which increases transcription of anti-inflammatory cytokines
what do pdes do?
specific pdes control cAMP or cGMP or some both.
what does roflumilast do to pde4?
roflumilast can inhibit PDE4 which raises cAMp inside the cell, good for copd by inhibiting inflammatory cell production (TNFa), inhibition of fibrosis by inhibiting activity of fibroblasts to produce collagen, and relaxation of airway sm.
what are the biological effects of rofluminast in vitro ?
decreased release of inflammatory cytokines, mediators chemotactic factors from cell. reduced neutrophil migration. increased apoptosis, expression of anti-inflammatory cytokines
what are biological activity of roflumiast in vivo?
reduce the accumulation of neutrophils in bronchoalveolar lavage fluid. rofluminast also prevented lung infiltration.
also improves lung function in copd models - smoking, infection, elastin
what are desired characteristics of rofluminast?
Good Pharmacokinetics-orally active
Good clinical efficacy (based on good pharmacodynamics- gets to and interacts with target)
Few/tolerable adverse effects
what are the pharmacokinetic properties of rofluminast ?
Converted by cytochrome P450 (CYP) 3A4 and 1A2 to active metabolite roflumilast N-oxide (90% of total activity)
Rapidly and almost completely absorbed after oral administration, maximum plasma concentrations within ~1 h,
Absolute bioavailability is ~80% as an immediate-release tablet
The therapeutic dose is 500 mg, taken once daily. On repeated oral dosing with roflumilast 500 mg once daily free drug concentration of RF N-oxide in plasma is ~1–2 nM,
Plasma protein binding of RF N-oxide of approximately 97%
Drug interaction studies have shown that no dose adjustment of roflumilast 500 mg was required when co-administered with erythromycin, ketoconazole, midazolam, digoxin and the antacid Maalox®,
what is effect of rofluminast in presence of antimuscirinic and B adrenoreceptor agonist in exacerbations?
rofluminast reduces exacerbations singificantly compared to am, or B2 agonists.
in pre bronchodilator fev1 - treatment with rofluminast significant , whereas other have negative effects. active when in combination with standard bronchodilator therapy to increase FEV1
