In support of that article and to aid the discussion, Christos Argyropoulos has stepped up to the blogger plate to provide some color on pentoxifylline.
In wild anticipation of next week’s #NephJC on Pentoxifylline (PTX) let’s go over some of the known facts about the drug:
- It is a non-selective phosphodiesterase inhibitor. PDEs are enzymes that inactivate cyclic nucleotides and have been organized in 11 families (Table 1 ) based on sequence, structural and pharmacological considerations. Inhibition of PDE4 by PTX (Figure 1)  increases cAMP & stimulates PKA activity.
- Activation of PKA leads to phosphorylation of the cAMP response element binding protein (CREB) which in turn leads to suppression of the TNF-a[2,3] synthesis at the transcriptional level
- Inhibition of cAMP production by these phosphodiesterases has a broad range of immunomodulatory effects (Table 2)
- The drug also affects red cell deformability and favorably affects microcirculatory blood flow
- “Mainstream” indications: intermittent claudication, vascular dementia, sickling crises, acute alcoholic hepatitis
- Pharmacokinetics: bioavailability (10-30%), elimination (mostly renal as 50-80% of the drug is recovered in the urine), half life (24-48 mins)
|Figure 1: Pentoxifylline (white) complexed with PDE4 (ribbons). Also shown are the Mg2+ and Zn2+ cofactors of PDE4 (spheres)|