Chapter 41: Pentoxifylline

Web Chapter 41


Pentoxifylline (PTX) is a methylxanthine derivative with multiple hemorheologic and immunomodulatory properties. PTX is available as a generic formulation or a brand name drug (Trental, 400-mg tablets). This drug has been used for almost 40 years in humans with intermittent claudication caused by peripheral and cerebrovascular atherosclerotic disease and for at least 10 years in veterinary medicine to treat a variety of conditions. The list of conditions for which PTX has been found to be potentially beneficial in dogs has grown rapidly (Marks et al, 2001). The drug is rarely used in feline dermatology (Nichols et al, 2001). This chapter reviews the use of PTX in small animal dermatology.

Properties of Pentoxifylline

PTX is a nonspecific phosphodiesterase (PDE) inhibitor. Through its hemorheologic properties, PTX changes the conformation of red blood cells and improves microcirculatory blood flow and tissue oxygenation. Aged red blood cells have rigid membranes because of reduced adenosine triphosphate levels and increased calcium levels. By increasing levels of cyclic adenosine monophosphate (cAMP, the second messenger of the β-adrenergic system) and by modulating intracellular calcium levels, PTX increases red blood cell deformability. Besides affecting red blood cells, PTX also exerts beneficial effect on platelets by decreasing platelet aggregation and blood viscosity. Once again, this is caused by the inhibition of PDE and the decrease in cAMP degradation. It is interesting to note that PTX restores normal cAMP levels and has an effect on aggregation only in conditions in which the platelets are hyperaggregable and have altered levels of cAMP. PTX does not appear to affect normal platelets and therefore does not prolong bleeding. Therefore it is not necessary to discontinue PTX therapy before surgical procedures.

PTX exerts multiple beneficial effects on the inflammatory cascade by increasing intracellular cAMP levels and decreasing synthesis of tumor necrosis factor-α (TNF-α). Since TNF-α is a proinflammatory cytokine with a broad spectrum of actions, its decrease leads to multiple antiinflammatory effects. These include decreased release of other proinflammatory cytokines such as interleukin-1 (IL-1) and IL-6, decreased leukocyte adhesion and aggregation, decreased neutrophil degranulation and superoxide release, inhibition of B-cell activation (by suppression of IL-6 synthesis), and inhibition of T-cell activation (through the CD23 and CD26 pathway) (Bruynzeel et al, 1995). Based on in vitro studies, the decrease of cytokine expression is dose dependent. The beneficial effects of PTX have been shown in numerous animal studies using models of ischemia-reperfusion and septic shock (Zhang et al, 1994). In these studies PTX significantly improved survival rates by both decreasing the inflammatory reaction and improving tissue oxygenation. Finally, PTX also improves wound healing by increasing fibroblast collagenases and decreasing collagen production, fibronectin, glycosaminoglycans, and fibroblast response to TNF-α.


The pharmacokinetic and pharmacodynamic properties of PTX have been well characterized in human patients. PTX is absorbed rapidly and extensively after oral administration (Marsella et al, 2000). After absorption from the gastrointestinal tract, it binds to the red blood cells, where it is reduced immediately to metabolite 1 (M1). This transformation is reversible, and M1, which also binds to the erythrocyte membrane, serves as a reservoir for PTX. The other six metabolites are formed in the liver and appear in plasma soon after dosing. Extensive enterohepatic recycling occurs, and more than 90% of the absorbed drug is excreted in the urine in the form of metabolites. M1 and M5 are the major metabolites, and the plasma levels of these compounds are five and eight times greater, respectively, than that of the parental drug. Bioavailability in humans averages 20% to 30% and is affected by food. Excretion is almost completely urinary. M1 and M5 are present in the highest concentration in the urine, whereas no PTX is found in the urine.

Only a few studies have been done in dogs to evaluate the disposition of PTX and its active metabolites. In one study (Marsella et al, 2000) PTX was found to be absorbed and eliminated rapidly after oral administration. Peak plasma concentration for PTX (15 mg/kg) was achieved 30 minutes after oral administration. Concentrations declined rapidly, and no drug was detected after 4 hours. After intravenous administration (15 mg/kg), elimination proceeded rapidly, and no drug was detectable after 3 hours. Peak plasma concentration of M1 and M5 after intravenous and oral administration was achieved after 20 minutes and 60 minutes, respectively. Mean bioavailability after oral administration ranged from 15% to 32% among treatment groups and was not affected by the presence of food. Higher plasma PTX concentrations and apparent bioavailability were observed after oral administration of the first dose than after the last dose during the 5-day treatment regimens. It was concluded that oral administration of PTX at 15 mg/kg resulted in plasma concentrations similar to those produced by therapeutic doses in humans and that a three-times-daily dosing regimen was the most appropriate. No adverse effects were observed.

In another study (Rees et al, 2003) PTX was readily metabolized and bioavailable (50% ± 26%). Both active metabolites (M1 and M5) were detectable, with M5 predominating. Human drug therapeutic concentrations (1000 ng/ml) were present for 170 ± 24 minutes following intravenous administration and 510 ± 85 minutes after oral dosing. This study emphasized the large variability in absorption and disposition of PTX in dogs. None of the dogs experienced any adverse effects after PTX administration. No hematologic effects were detected.

Indications for Use in Veterinary Dermatology

PTX has been used to treat a variety of dermatologic conditions, with success dependent on dose. Since several of the conditions have a waxing and waning course and many of the studies done were open studies, a scientific evaluation of the efficacy of the drug was not always possible. Nevertheless, the list of dermatologic diseases for which PTX has been reported to be beneficial is quite extensive.


Canine familial dermatomyositis is an inflammatory disease in which microvascular vasculopathy is thought to play a role. Therefore dermatomyositis was one of the first dermatologic diseases in which PTX was tried and reported to have useful effects. In the management of dermatomyositis cases PTX usually is considered as a steroid-sparing agent and rarely as the only form of treatment (Rees et al, 2003). The advantage of using PTX is its better safety profile and lack of atrophogenic properties compared with glucocorticoids. The response to treatment is variable and typically slow (2 to 3 months). Historically a large range of dosages and treatment regimens have been suggested. Recommended dosage ranges from 10 to 20 mg/kg orally every 8 to 12 hours depending on the severity of the disease. Based on a study by Rees and Boothe (2003) it appears that a dosage of 25 mg/kg twice daily resulted in positive clinical response (four complete and six partial responses in the 10 dogs treated). In that study the authors investigated whether a direct correlation could be established between concentrations of PTX and its metabolites and clinical response; they concluded that, because of the variability in disposition and metabolite formation among individual dogs, monitoring of PTX concentration did not offer a therapeutic advantage.

< div class='tao-gold-member'>

Only gold members can continue reading. Log In or Register to continue

Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Chapter 41: Pentoxifylline

Full access? Get Clinical Tree

Get Clinical Tree app for offline access