Rosanna Marsella,     Gainesville, Florida

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.

Pharmacokinetics

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.

Adverse Effects

In contrast to other methylxanthines, PTX has few cardiac effects. PTX can be a gastric irritant, and in humans the main adverse effect is gastrointestinal upset (e.g., vomiting and diarrhea). Other reported adverse effects in humans are angina/chest pain, agitation, dizziness, headache, and tremors. Adverse effects are dose related and can be decreased by lowering the dose. Dogs appear to tolerate oral PTX very well, even on an empty stomach. Gastrointestinal upset can be seen, although it is not common. No significant changes in chemistry values have been reported in dogs receiving PTX (Rees and Boothe, 2003). There are anecdotal reports of transient cutaneous flushing and erythematous macules in short-coated dogs.

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.