Tomorrow is another exciting edition of #NephJC. We will be discussing pentoxifylline in diabetic nephropathy. There is a summary of the article at
NephJC.com.
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.
Joel
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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 [1]) based on sequence, structural and pharmacological considerations. Inhibition of PDE4 by PTX (Figure 1) [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[1])
- The drug also affects red cell deformability and favorably affects microcirculatory blood flow
- “Mainstream” indications: intermittent claudication, vascular dementia, sickling crises, acute alcoholic hepatitis
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| Figure 1: Pentoxifylline (white) complexed with PDE4 (ribbons). Also shown are the Mg2+ and Zn2+ cofactors of PDE4 (spheres) |
- Pharmacokinetics: bioavailability (10-30%), elimination (mostly renal as 50-80% of the drug is recovered in the urine), half life (24-48 mins)
